bims-proteo Biomed News
on Proteostasis
Issue of 2026–06–28
43 papers selected by
Eric Chevet, INSERM
  1. Heat stress reveals bidirectional cross talk between the heat shock response and UPRER in C. elegans.
  2. Small bites for big problems: stepwise aggregate degradation by autophagy.
  3. Selenoprotein S plays a role in translation and membrane protein biogenesis.
  4. PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
  5. IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
  6. Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.
  7. Molecular Glues Recruiting RNF213 As an E3 Ligase for Targeted Protein Degradation: A Minimal Dibromoacetamide Warhead As a Recruitment Ligand.
  8. ISGylation mechanism uncovers conformational specificity for HECT-family E3 ligase HERC5.
  9. An isotype-specific phosphorylation of Hsp90 rewires co-chaperone regulations.
  10. A real-time FRET ubiquitin transfer assay for quantitative characterization of ternary complexes in targeted protein degradation.
  11. The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
  12. Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
  13. A ribosomal kinetic checkpoint governs selective mRNA recruitment.
  14. The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
  15. FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
  16. A Subset of Caveolin-1 Interacts with a Fraction of Acyl-CoA:Cholesterol Acyltransferase 1 (ACAT1/SOAT1) at an Endoplasmic Reticulum Subdomain to Attenuate Cholesteryl Ester Biosynthesis.
  17. Substrate-induced assembly and functional mechanism of the membrane protein insertase SecYEG-YidC.
  18. Endoplasmic Reticulum Structure as a Fundamental Physical Constraint on Ribosome Density.
  19. A Type II CDK6 Degrader Enables Cellular Targeting beyond the Limits of Type II Inhibition.
  20. UFMylation orchestrates kidney development through YAP stabilization.
  21. Inhibition of AGR2 triggers secretion of GRP78 and sensitizes gastroesophageal junction adenocarcinoma cells to ER stress.
  22. Pericentrosomal Redistribution of the Endoplasmic Reticulum Ensures Organelle Symmetric Inheritance and Mitotic Progression.
  23. Cross-species systems analysis distinguishes inflammatory remodeling from primary mucus secretory failure in inflammatory bowel disease.
  24. Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
  25. Csf1 facilitates adaptive membrane lipid remodeling linked to ER-plasma membrane contact sites.
  26. RNASET2 degrades mRNAs that protect against lipotoxicity.
  27. Allostery is a widespread cause of loss-of-function variant pathogenicity.
  28. ASAP-ID: Proximity labelling with small tags.
  29. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
  30. Compound BOZA attenuates fibrosis in systemic sclerosis by modulating the PERK-HNRNPA1 axis.
  31. Adaptor-mediated interaction between Kv1.3 and Nedd4-2 E3 ubiquitin ligase.
  32. Longitudinal monitoring of cytoplasmic RBP-RNA interactions and transcriptome in living cells by engineered protein nanocages.
  33. Cellular assembly and functional resilience of the mammalian RNA exosome.
  34. ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
  35. Mixed-class J-domain protein scaffolds promote expanded aggregate handling and multivalent Hsp70 engagement during functional disaggregase assembly.
  36. The role of RNA modifications in cancer translational control.
  37. Inhalable Polymeric PROTAC Nanococktail for Targeted Protein Degradation in Idiopathic Pulmonary Fibrosis.
  38. Reversible suppression of autophagy in a mouse model reveals neuronal resilience.
  39. A unified platform for the rapid assembly of glutarimides for Cereblon E3 ligase modulatory drugs.
  40. A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
  41. Alternate RNA decoding results in stable and abundant proteins in mammals.
  42. Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation.
  43. Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
  1. G3 (Bethesda). 2026 Jun 22. pii: jkag141. [Epub ahead of print]
    Heat stress reveals bidirectional cross talk between the heat shock response and UPRER in C. elegans.
    Athena Alcala, Toni Castro Torres, Rebecca Aviles Barahona, Phillip A Frankino, Ryo Higuchi-Sanabria, Gilberto Garcia.
      Organisms rely on coordinated stress responses to maintain cellular homeostasis. Perhaps the best-known example of multiple stress inputs converging onto a single response is the integrated stress response, which reduces global translation under various stressed conditions to reduce the protein folding burden of the cell. Similarly, most stress responses generally involve coordination of additional protein homeostasis (proteostasis) pathways, including increased expression of chaperones to refold proteins, as well as activation of clearance mechanisms, such as autophagy and the ubiquitin proteasome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and endoplasmic reticulum (ER) chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPRER). Using robust transcriptional reporters in the Caenorhabditis elegans model system, we explore a noncanonical activation of the UPRER under heat stress by the coordinated effects of XBP-1 and HSF-1. We further investigate inter-tissue communications of stress whereby neuronal or glial activation of the UPRER can result in heterotypic enhancement of the HSR in peripheral cells and can increase thermotolerance. This work highlights the complex convergence of cellular stress responses, a phenomenon that may reflect a general strategy wherein localized stress can activate numerous proteostasis pathways to prevent whole-cell and whole-organism damage.
    Keywords:  endoplasmic reticulum unfolded protein response; heat stress; heat-shock response
    DOI:  https://doi.org/10.1093/g3journal/jkag141
  2. Biochem Soc Trans. 2026 Jun 24. 54(6): 803-814
    Small bites for big problems: stepwise aggregate degradation by autophagy.
    Mark S Hipp, Mario Mauthe.
      Protein aggregates are a pathological hallmark of diverse disorders, including many neurodegenerative diseases, but also cardiometabolic disease and cancer. While the ubiquitin-proteasome system efficiently removes many soluble misfolded proteins, large or persistent assemblies often require the autophagy-lysosome pathway for their degradation. In the present mini-review, we summarize our knowledge of aggrephagy, the selective clearance of protein aggregates by autophagy, and discuss two recent manuscripts that argue that some aggregates must be primed for autophagosomal degradation, through chaperone-mediated remodeling. Aggrephagy substrates are defined by aggregate architecture, biophysical state, surface accessibility, and the physical constraints of membrane capture. These features help to explain why recruitment of selective autophagy receptors is necessary yet insufficient for clearance. Receptor clustering is required to concentrate early autophagy factors to establish initiation hubs, but successful degradation often requires upstream generation of smaller 'aggrephagy-competent' cargo units, which contain autophagy receptor clusters that successfully initiate autophagosome formation. Recent work supports a model in which larger aggregates are cleared through stepwise degradation enabled by prior remodeling steps that involve p97/VCP-driven disintegration or a chaperone module (DNAJB6-HSP70-HSP110) cooperating with the proteasomal 19S regulatory particle.
    Keywords:  autophagy; cellular protein quality control; molecular chaperones; piecemeal; selective autophagy receptors
    DOI:  https://doi.org/10.1042/BST20250460
  3. bioRxiv. 2026 Jun 16. pii: 2026.06.08.725543. [Epub ahead of print]
    Selenoprotein S plays a role in translation and membrane protein biogenesis.
    Farid Ghelichkhani, Mariia A Kapitonova, Atinuke Odunsi, Erfan Rahmani, Omar G Rosas Bringas, Mohammed Hanzala Kaniyar, John LaCava, Sharon Rozovsky.
      Human selenoprotein S (selenos) is part of the integrated cellular stress response and linked to protein quality control and signaling pathways. Consequently, genetic polymorphisms of selenos are associated with increased risk for diabetes, dyslipidemia, and cardiovascular diseases. Determining the specific roles of selenos in these cellular pathways and diseases has been challenging, as selenos associates with a wide range of protein complexes. Thus, to map the cellular functions of selenos and uncover their interconnections, we used affinity purification and in vivo crosslinking to stabilize transient protein interactions, followed by proteomics to record the resulting selenos interactome. Through mapping of selenos protein partners, we found evidence that selenos associates with complexes responsible for the insertion of membrane proteins into the ER bilayer and their connected quality control components. Furthermore, selenos is also part of metabolic, trafficking, and mitochondrial pathways. Notably, proteins involved in translation preferentially associate with selenos when its C-terminal intrinsically disordered segment containing the redox-active motif is accessible. Together, these results identify the C-terminal redox loop of selenos as a central interaction hub connecting translation with ER membrane protein biogenesis and quality control.
    DOI:  https://doi.org/10.64898/2026.06.08.725543
  4. J Cell Biol. 2026 Sep 07. pii: e202507087. [Epub ahead of print]225(9):
    PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
    Nicala Jenkins, Zainab Adamji, Maria R Narciso, Nourhan R Almasri, Sharifa Lomiyev, Roberto J Botelho.
      Lysosomes clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and promotes lysosome fission since lysosomes coalesce into larger, but fewer, organelles in its absence. Here, we reveal a role for PIKfyve in regulating ER dynamics. We show the ER is less reticulated and motile in cells inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin's FYVE domain. Our findings reveal that PIKfyve balances phosphoinositides at ER-lysosome contact sites to govern ER properties and have significant implications for our understanding of PIKfyve function and of diseases linked to its dysfunction.
    DOI:  https://doi.org/10.1083/jcb.202507087
  5. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2610001123
    IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
    Dongyue Liu, Yu Li, Shuai Huang, Yufang Xu, Lei Sun, Wen Li, Cahir J O'Kane, David C Rubinsztein, Bingwei Lu, Shuangxi Li.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.
    Keywords:  IRE1; TDP-43/TARDBP; ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1073/pnas.2610001123
  6. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731146. [Epub ahead of print]
    Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.
    Christopher J Bott, Martyna O Iwaniek, James E Casanova.
      Lysosomal membrane damage triggers a multi-stage repair response essential for cellular homeostasis. Here we identify the oxysterol-binding protein-related protein ORP3 as a critical mediator of late-stage lysosomal membrane repair. Following lysosomal damage induced by L-leucine-leucine methyl ester (LLOME) or cationic amphiphilic drugs (CADs), ORP3 is phosphorylated and recruited to ER-lysophagosome contact sites via a signaling cascade initiated by lysosomal membrane ubiquitination, TAK1, p38 MAPK, and, to a lesser extent, IKK. p38-dependent phosphorylation promotes direct interaction between ORP3 and LC3B, which together with PI(4,5)P₂ binding, is required for autophagic lysosome recruitment. ORP3 depletion impairs late-stage lysosomal recovery, elevates lysosomal lipid peroxidation, and reduces cell survival. A lipid transfer-deficient ORP3 mutant fails to restore lysosome function despite normal recruitment, indicating that ER-to-lysophagosome transfer of phosphatidylcholine by ORP3 is functionally required. ORP3 activity is subsequently terminated by VCP/p97-mediated deubiquitination of lysosomes. These findings define ORP3 as a MAPK regulated lipid transfer protein during the late autophagic phase of the endolysosomal damage response.
    Summary: Lysosomal membrane damage triggers ubiquitination that activates a TAK1-p38 signaling cascade, phosphorylating the lipid transfer protein ORP3 and recruiting it to damaged lysosomes via LC3B interaction. ORP3-mediated phosphatidylcholine transfer from the ER is essential for late-stage lysosomal repair and cell survival.
    Abstract Figure:
    DOI:  https://doi.org/10.64898/2026.06.09.731146
  7. J Am Chem Soc. 2026 Jun 23.
    Molecular Glues Recruiting RNF213 As an E3 Ligase for Targeted Protein Degradation: A Minimal Dibromoacetamide Warhead As a Recruitment Ligand.
    Jingyi Jiang, Yubin Chen, Rui Wan, Chaoming Huang, Tao Xiang, Chuixing Luo, Jianxiong Deng, Zhang Zhang, Tongzheng Liu, Yi Tan, Zhengqiu Li.
      Targeted protein degradation (TPD) is a promising therapeutic strategy, yet its application remains constrained by the limited repertoire of available E3 ubiquitin ligases, primarily CRBN and VHL. Here, we identify RNF213 as a recruitable E3 ligase that mediates protein degradation induced by molecular glue degraders. We developed CYB-5067 by equipping the pan-FGFR inhibitor Infigratinib with a minimal dibromoacetamide covalent warhead. This covalent molecular glue recruits RNF213 to potently degrade FGFR1-4, with the strongest effect on FGFR2 (DC50 = 27 nM, Dmax = 96%). CYB-5067 outperforms parent inhibitors in vitro (IC50 = 3.8 nM) and shows comparable antitumor efficacy in vivo (TGI = 94.6%), with sustained target suppression and no apparent hook effects under the tested conditions. Notably, the dibromoacetamide warhead is transplantable, enabling selective degradation of other challenging targets such as WEE1 and CDK12, which regulate cell-cycle progression and transcription. This offers a rational strategy for creating molecular glues. Our work identifies RNF213 as an exploitable ligase for TPD and establishes covalent molecular glues as a modular platform. This strategy expands the scope of degrader design beyond conventional E3 ligases, offering an avenue for developing potent and selective therapeutics.
    DOI:  https://doi.org/10.1021/jacs.6c03429
  8. Cell Rep. 2026 Jun 19. pii: S2211-1247(26)00643-1. [Epub ahead of print]45(7): 117565
    ISGylation mechanism uncovers conformational specificity for HECT-family E3 ligase HERC5.
    Pritiranjan Sahoo, Gloria Grace Parmar, Dipti Ranjan Lenka, Mohini Sherawat, Bhagya Shri Trivedi, Atul Kumar.
      Interferon-stimulated gene 15 (ISG15), composed of two ubiquitin-like domains, plays a critical role in antiviral immunity. Although the ubiquitination mechanism is well established, the mechanisms governing ISG15 transfer, particularly from E2 to E3 and subsequent lysine conjugation, remain unknown. Here, we reveal that UbcH8(E2)∼ISG15 exhibits striking specificity for HECT-family E3 ligases (particularly HERC5) but is inactive with RING or RBR E3. In contrast, UbcH8∼Ub preferentially engages RBR E3, indicating a switched E2-E3 specificity depending on the conjugated ubiquitin-like modifier. Structural and biochemical studies uncover how a closed conformation of UbcH8∼ISG15 enables trans-thiolation mediated by selective HECT-family E3 ligases. We further demonstrate that HERC5's C-lobe specifically recognizes donor ISG15 for lysine conjugation, explaining its exclusive ISGylation activity and lack of ubiquitination function. These findings delineate the molecular basis of ISG15 conjugation and reveal how its pathway has evolved distinct mechanisms from ubiquitination, offering new avenues for therapeutic intervention.
    Keywords:  CP: molecular biology; ubiquitination, ISGylation, HECT, HERC5, ISG15, structural biology, biochemistry, biophysics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117565
  9. J Biol Chem. 2026 Jun 23. pii: S0021-9258(26)02164-2. [Epub ahead of print] 113292
    An isotype-specific phosphorylation of Hsp90 rewires co-chaperone regulations.
    Tisya Banerjee, Elisabetta Moroni, Maximilian Riedl, Giorgio Colombo, Johannes Buchner.
      The molecular chaperone Hsp90 is a major protein folding factor in the cytosol of eukaryotic cells. Its conformational cycle is regulated by various co-chaperones and post-translational modifications (PTMs) such as phosphorylation. Most of the phosphorylation sites are conserved between the two isoforms of human Hsp90, Hsp90α and Hsp90β. The analysis of the function of these sites has revealed general functional principles of Hsp90. To what extent isoform-specific phosphorylation regulates Hsp90 function is less well understood. Here, we explore the effect of the phosphorylation of a residue (threonine 446) specific for the constitutionally active isoform Hsp90β. Since T446 is bioinformatically predicted to be phosphorylated by kinases regulating the intrinsic stress response (ISR), this modification links Hsp90 function to the ISR status of the cell in an isotype-specific manner which renders Hsp90 unresponsive to the co-chaperone-mediated modulation of its ATPase activity and consequently affects client maturation. Hsp90β reverts to baseline ATPase-driven chaperoning activity which is no longer intensively regulated by co-chaperones and results in the rewiring of Hsp90-mediated protein quality control.
    Keywords:  Molecular chaperones; glucocorticoid receptor; integrated stress response; phosphorylation; posttranslational modification; protein quality control
    DOI:  https://doi.org/10.1016/j.jbc.2026.113292
  10. Cell Rep Methods. 2026 Jun 23. pii: S2667-2375(26)00206-7. [Epub ahead of print] 101505
    A real-time FRET ubiquitin transfer assay for quantitative characterization of ternary complexes in targeted protein degradation.
    Corey H Yu, Vi Dougherty, Dongwen Lv, Pirouz Ebadi, Shikha Dubey, Digant Nayak, Anindita Nayak, Daohong Zhou, Shaun K Olsen, Dmitri N Ivanov.
      Inhibiting or redirecting E3 ubiquitin ligase activity with drug-like small molecules is of growing therapeutic interest, yet broadly applicable and robust assays for quantifying E3-catalyzed ubiquitination remain limited. Here, we present a real-time, high-throughput fluorescence assay utilizing purified, FRET-active E2-Ub conjugates to monitor ubiquitin transfer. This assay is highly versatile, requiring no engineering of the target protein or ligase, thereby accelerating assay development and minimizing the risk of artifacts. The single-step, single-turnover nature of the reaction enables rigorous and quantitative analysis of ubiquitination kinetics. We show that this assay can be used to measure key degrader characteristics, including degrader affinity for the target protein, degrader affinity for the ligase, affinity of ternary complex assembly, and catalytic efficiency of the ternary complex. The high sensitivity and accuracy of this comprehensive, single-assay approach to ternary complex characterization will empower the discovery and optimization of heterobifunctional degraders and molecular glues.
    Keywords:  CP: biotechnology; E3 ubiquitin ligases; FRET; PROTACs; fluorescence resonance energy tranfer; high-throughput screening; molecular glues; targeted protein degradation; ternary complexes; ubiquitin transfer kinetics
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101505
  11. bioRxiv. 2026 Jun 10. pii: 2026.06.08.730917. [Epub ahead of print]
    The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
    Michelle A Johnson, Richa Khanna, Sirisha Mukkavalli, Ly Nguyen, Malavika Raman.
      Stress granules form in response to diverse cellular perturbations to sequester translation components until the stress is resolved. Stress granules are composed of RNA-protein assemblies in membrane delimited structures and must be rapidly disassembled to release components to allow translation to resume. Disassembly of stress granules formed in response to heat stress is dependent on ubiquitiylation of stress granule components such as G3BP1. Ubiquitylation of stress granule proteins recruits the AAA-ATPase p97 (also known as VCP) to enable ubiquitin-dependent disassembly of these structures. Loss of p97 activity leads to the persistence of stress granules and is implicated in several age-related neurodegenerative diseases. Here we show that p97 recruitment to stress granules is dependent on its ubiquitin binding co-factor p47. p47 translocates to stress granules in response to a variety of cellular stressors and is required for the recruitment of p97 to stress granules. Loss of p47 leads to an inhibition in stress granule disassembly. We further show that p47 associates with G3BP1 in response to heat stress in a ubiquitin-dependent manner. Taken together our data adds to the growing list of p97 adaptors that are implicated in the recruitment of p97 for dissolution of stress granules.
    DOI:  https://doi.org/10.64898/2026.06.08.730917
  12. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731205. [Epub ahead of print]
    Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
    Austin K Murchison, Julia C Heiby, Hansen Tao, Matthew J Matrongolo, Alessandro Ori, Monther Abu-Remaileh.
      Zinc is an essential structural and enzymatic cofactor for roughly 10% of proteins, including transcription factors, metabolic enzymes, and cytoskeletal components. It also supports critical functions across organelles such as gene regulation in the nucleus, protein folding in the endoplasmic reticulum, and energy production and antioxidant defense in mitochondria. Despite these indispensable roles, the cellular mechanism that recycles zinc to maintain homeostasis during zinc deficiency remains poorly understood. Here, we identify a biphasic response to zinc limitation, which involves the rapid degradation of the zinc-storing metallothionein followed by the degradation, in an autophagy-dependent manner, of other zinc-binding proteins. We show that metallothionein is rapidly imported into the mitochondria to be degraded by the mitoprotease LONP1. Zinc starvation leads to severe mitochondrial dysfunction and metallothionein degradation allows local zinc release to alleviate nutrient stress. Our results reveal a non-canonical, mitochondria-mediated degradation pathway for a nutrient-storing protein that mobilizes zinc locally to maintain metabolic homeostasis and establish mitochondria as active hubs for nutrient recycling.
    DOI:  https://doi.org/10.64898/2026.06.09.731205
  13. bioRxiv. 2026 Jun 13. pii: 2026.06.12.731988. [Epub ahead of print]
    A ribosomal kinetic checkpoint governs selective mRNA recruitment.
    Masaaki Sokabe, Carlos Alvarado, Christopher P Lapointe, Nancy Villa, Joseph D Puglisi, Christopher S Fraser.
      Translation initiation begins with recruitment of mRNA to the ribosome, yet how mRNA engagement is converted into productive initiation remains unclear. Using real-time fluorescence assays with purified components, we show that mRNA recruitment proceeds through a branched kinetic pathway on the 40S subunit. Following rapid sampling, mRNAs partition into either a productive accommodated state or an arrested state that stabilizes ribosome binding before accommodation. mRNA structure, eIF3, and eIF3j bias recruitment toward arrest, whereas eIF4F promotes accommodation in an ATP-dependent manner coupled to displacement of eIF3j from the mRNA entry channel. Unstructured mRNAs accommodate independently of eIF4E, whereas structured mRNAs require an upstream eIF4E-dependent step, enabling selective recruitment under limiting eIF4E. Arrested complexes can convert directly into the accommodated state without dissociation, revealing a reversible standby intermediate poised for activation. Together, our findings establish mRNA accommodation as a ribosome-intrinsic checkpoint governing initiation and provide a framework for selective translation.
    DOI:  https://doi.org/10.64898/2026.06.12.731988
  14. Dev Cell. 2026 Jun 25. pii: S1534-5807(26)00198-X. [Epub ahead of print]
    The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
    Catherine M Heffner, Georgina P Starling, Lorian C Straker, Philippa C Hawes, Adrian M Isaacs, Jeremy G Carlton.
      Maintenance of plasma membrane integrity is essential for compartmentalization of the cytosol and for cellular viability. Upon membrane damage, several factors including endosomal sorting complex required for transport-III (ESCRT-III) proteins, annexins, stress granules, lipids, and membrane fusion proteins are mobilized to orchestrate membrane repair. However, whether these factors operate independently or act together is unclear. Here, using human cell lines, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and annexin proteins to sites of plasma membrane damage. We show that annexin proteins are recruited immediately and form a plug at the damage site, restricting membrane permeability. We find that ESCRT-III assembles later and acts to release plug-containing damaged membranes from the cell. Further, frontotemporal dementia (FTD)- and amyotrophic lateral sclerosis (ALS)-associated mutations in the ESCRT-III protein, CHMP2B, and the annexin protein, ANXA11, compromise plasma membrane repair, suggesting that defects in this process may contribute to these pathologies. These data present an integrated "sealing and healing" model of membrane repair.
    Keywords:  ALS; ANXA11; CHMP2B; ESCRT-III; FTD; annexin; membrane repair; pore-forming toxin
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.014
  15. Sci Adv. 2026 Jun 26. 12(26): eaec8143
    FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
    Qian Zhang, Hangyu Dong, Yayun Jiang, Zihao Wang, Jiasheng Li, Ye Tian.
      Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in Caenorhabditis elegans, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPRmt). Loss of fubl-3 disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPRmt, and extend lifespan. Notably, human FUBP1 rescues fubl-3 mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8143
  16. Biomolecules. 2026 Jun 08. pii: 838. [Epub ahead of print]16(6):
    A Subset of Caveolin-1 Interacts with a Fraction of Acyl-CoA:Cholesterol Acyltransferase 1 (ACAT1/SOAT1) at an Endoplasmic Reticulum Subdomain to Attenuate Cholesteryl Ester Biosynthesis.
    Catherine C Y Chang, Toyoshi Fujimoto, Yoshio Yamauchi, Yasuomi Urano, Ta Yuan Chang.
      Caveolin-1 is a scaffolding protein of caveolae, flask-shaped membrane microdomains involved in diverse cellular processes. Caveolae are primarily localized to the plasma membrane, the trans-Golgi network, and mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). Most enzymes involved in cholesterol biosynthesis reside in the ER, and although caveolin-1 avidly binds cholesterol, its role in cholesterol trafficking remains unclear. Acyl-coenzyme A:cholesterol acyltransferases (ACAT1 and ACAT2) convert free cholesterol into cholesteryl esters for storage, with ACAT1 serving as the predominant isoenzyme in most cell types. ACAT1 is an ER-resident protein, with a fraction associated with specialized ER subdomains, including the MAM. Here, we report that a subset of caveolin-1 molecules appears to be associated with a fraction of ACAT1 in ER subdomains. Using immunoprecipitation under detergent conditions, immunoadsorption of MAM-enriched membranes under detergent-free conditions, and electron microscopy, we provide evidence consistent with an association between a subset of caveolin-1 molecules and ACAT1. Functionally, in mouse embryonic fibroblasts, we show that genetic ablation of caveolin-1 significantly increases the esterification of low-density lipoprotein-derived cholesterol, suggesting that caveolin-1 may attenuate ACAT1 activity. Collectively, these findings indicate that caveolin-1 may modulate cholesterol esterification and contribute to the regulation of cholesterol distribution among cellular membranes.
    Keywords:  acyl-CoA:cholesterol acyltransferase; caveolae; caveolin-1; cholesterol; cholesteryl oleate; endoplasmic reticulum; mitochondria-associated membranes; sterol O-acyltransferase; trans-Golgi network
    DOI:  https://doi.org/10.3390/biom16060838
  17. EMBO J. 2026 Jun 26.
    Substrate-induced assembly and functional mechanism of the membrane protein insertase SecYEG-YidC.
    Max Busch, Cristian Rosales-Hernandez, Michael Kamel, Yulia Schaumkessel, Eli O van der Sluis, Otto Berninghausen, Thomas Becker, Roland Beckmann, Alexej Kedrov.
      The Sec translocon and the YidC/Oxa1-type insertases universally mediate biogenesis of α-helical membrane proteins, but the molecular basis of their cooperation has remained disputed. Recent discovery of multi-subunit insertases assembled at the back of the translocon in fungi and higher eukaryotes has raised questions about the architecture and mechanism of the putative bacterial ortholog SecYEG-YidC. Here, we combine cryogenic electron microscopy with cell-free protein synthesis to visualize biogenesis of the SecYEG/YidC-dependent multipass membrane protein NuoK. The nascent chain of NuoK does not enter the lateral gate of SecYEG but instead crosses the translocon towards its back side, where YidC is recruited in the nascent substrate-dependent manner. The SecY-YidC interface promotes folding of the transmembrane helices before insertion, consistent with thermodynamic principles of membrane protein folding. YidC forms extensive contacts with the nascent chain, suggesting its key role in the insertion event. These findings provide mechanistic insight into membrane protein insertases, support evolutionary conservation of a gate-independent insertion route, and expand current models of membrane protein biogenesis.
    DOI:  https://doi.org/10.1038/s44318-026-00837-6
  18. Biophys J. 2026 Jun 22. pii: S0006-3495(26)00450-9. [Epub ahead of print]
    Endoplasmic Reticulum Structure as a Fundamental Physical Constraint on Ribosome Density.
    Benjamin Tang.
      Recent work has shown an increasing interest in understanding the structure of the endoplasmic reticulum (ER) and how ribosomes are displayed on it. While there has been much work on the biological factors that affect ER structure and ribosome density, we have not seen work exploring how the later two are related. Here we present a diffusion-limited model that shows how the geometry of the ER imposes fundamental constraints on the capture efficiency of ER-bound ribosomes, and in doing so explains the qualitative difference between ribosome densities on the rough and smooth ER. First, we find that flat sheets and a matrix of tubules have distinct regimes where the capture efficiency of one geometry is greater than the other. Then, we show how these different regimes strongly constrain the experimentally observed differences in ribosome densities on the structures of the ER. In particular, fewer ribosomes are needed on tubules, while for flat sheets, more ribosome coverage at biologically relevant separation distances is needed to match the same capture efficiency. The model further predicts that depending on the downstream life of the translated protein and overall demand for protein expression, the cell will utilize one structure of the ER over another. Predictions are compared with experimental data.
    DOI:  https://doi.org/10.1016/j.bpj.2026.06.024
  19. J Am Chem Soc. 2026 Jun 26.
    A Type II CDK6 Degrader Enables Cellular Targeting beyond the Limits of Type II Inhibition.
    Ji Hyeon Kim, Caitlin E Mills, Zuzanna Kozicka, Daniel C Scott, Cyrus Jin, Zixuan Jiang, Brendan G Dwyer, Qixiang Geng, Sean T Toenjes, Woong Sub Byun, Dina ElHarouni, Hongyu Li, Keith L Ligon, Abby M Thornhill, Hannah M Jones, Bryan A Romero, Stephen M Hinshaw, Benjamin L Ebert, Brenda A Schulman, Katherine A Donovan, Eric S Fischer, Nathanael S Gray.
      PROTACs are commonly developed by linking E3 ligase-recruiting ligands to established inhibitors of a protein target, often resulting in degraders that retain enzymatic inhibition. Type II inhibition of cyclin-dependent kinases (CDKs) has been challenging, as reported compounds generally exhibit weak biochemical potency and limited cellular activity. Consistent with these limitations, most reported CDK degraders have been derived from type I ATP-competitive inhibitors. Here, we explored whether targeted protein degradation could enable functional CDK targeting from a type II kinase scaffold. Using the multikinase inhibitor regorafenib as a starting scaffold, we generated a focused library of CRL4CRBN-recruiting bifunctional molecules and profiled their degradation activity using quantitative mass spectrometry-based proteomics. This analysis unexpectedly revealed CDK5 and CDK6, kinases not inhibited by the parent scaffold, as degradation targets. Optimization of this series led to JHK-02-108-2, a selective CDK6 degrader that does not display a hook effect and promotes potent CDK6 degradation despite weak CDK6 binding and negligible CDK6 inhibition. In cellular models of acute myeloid leukemia (AML) and glioblastoma, JHK-02-108-2 induced sustained G1 arrest and reduced phosphorylation of the retinoblastoma protein. Interestingly, subtle modifications in PROTAC architecture redirected degradation selectivity, yielding JHK-02-102-1 as a selective type II CDK5 degrader derived from the same scaffold. Together, these findings establish the first type II inhibitor-derived selective CDK6 degrader and demonstrate that targeted protein degradation can enable functional CDK targeting from type II kinase scaffolds.
    DOI:  https://doi.org/10.1021/jacs.6c10277
  20. J Biol Chem. 2026 Jun 22. pii: S0021-9258(26)02157-5. [Epub ahead of print] 113285
    UFMylation orchestrates kidney development through YAP stabilization.
    Yi Chen, Longyi Wan, Wei Chen, You Zhou, Fuzhao Zhang, Junyan Zhang, Chenlu Zhang, Qian Liang, Yu Jiang, Ying Wang, Yajun Duan, Yu-Sheng Cong, Jiang Liu.
      The ubiquitin-like modifier UFM1 regulates diverse cellular processes through UFMylation. We previously demonstrated that UFMylation ligase UFL1 deficiency induces endoplasmic reticulum stress and culminates in kidney atrophy in adult mice, yet the critical UFMylation substrates and its function in organogenesis remains largely unexplored. Here, we report UFMylation is required for mammalian kidney development through Yes-associated protein (YAP) stabilization. Genetic ablation of Ufl1 in the murine kidney results in severe dysplasia, phenocopying the loss of YAP activity. We identified YAP as a substrate for UFMylation at lysine 76 (K76), which shields YAP from ubiquitin-proteasome degradation, thereby promoting its nuclear accumulation and transcriptional activation. Additionally, we discovered UFSP1, rather than UFSP2, acted as the primary protease for YAP de-UFMylation, whose depletion promoted YAP stabilization and activation. These findings establish UFMylation as a crucial post-translational mechanism licensing YAP-dependent transcription during development, reveal unexpected complexity in the regulation of YAP UFMylation, and implicate a previously unrecognized etiological pathway for kidney dysplasia.
    Keywords:  UFL1; UFMylation; UFSP1; UFSP2; YAP; kidney dysplasia
    DOI:  https://doi.org/10.1016/j.jbc.2026.113285
  21. Biochem Biophys Res Commun. 2026 Jun 20. pii: S0006-291X(26)00945-9. [Epub ahead of print]829 154181
    Inhibition of AGR2 triggers secretion of GRP78 and sensitizes gastroesophageal junction adenocarcinoma cells to ER stress.
    Quentin Bourgery, Nathalie Martin, Clémentine De Schutter, Stéphanie Flament, Fabrice Bray, Olivier Pluquet.
      The endoplasmic reticulum (ER) chaperone Anterior Gradient 2 (AGR2) is overexpressed in various adenocarcinomas, promoting tumor progression and chemoresistance. However, its exact role in modulating the Unfolded Protein Response (UPR) and remodeling the cancer cell secretome under proteotoxic stress remains poorly understood. Using shRNA-mediated silencing of AGR2 combined with high-throughput LC-MS/MS proteomic analysis in OE19 gastroesophageal junction adenocarcinoma cells, we profiled the global changes in protein secretion under basal and tunicamycin-induced ER stress conditions. Proteomic screening identified 75 differentially secreted proteins, with AGR2 depletion triggering a widespread up-secretion phenotype. Bioinformatic analysis revealed enrichment in pathways related to glycolysis, antigen processing and presentation, and extracellular matrix components. Notably, the ER-resident chaperone GRP78 was identified as a critical hub protein within the secretome. AGR2 knockdown downregulated intracellular GRP78 expression, and compromised UPR activation. Under ER stress, the absence of AGR2 triggered a massive secretion of GRP78 in the extracellular space, which correlated with a significantly increased sensitivity to tunicamycin-induced cell death. These findings identify AGR2 as a key regulator of GRP78 proteostasis and ER retention. By controlling the balance between intracellular retention and extracellular release of GRP78, AGR2 supports adaptive ER stress response and may contribute to tumor cell survival in gastroesophageal junction adenocarcinoma.
    Keywords:  AGR2 (Anterior gradient 2); ER stress; GRP78 (HSPA5); Secretome
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154181
  22. Adv Sci (Weinh). 2026 Jun 22. e76193
    Pericentrosomal Redistribution of the Endoplasmic Reticulum Ensures Organelle Symmetric Inheritance and Mitotic Progression.
    Xiangyu Xu, Yalin Liu, Rongyi Wang, Wenwen Xu, Hao Shi, Ning Huang, Junlin Teng, Jin Meng, Pengli Zheng, Jianguo Chen.
      Symmetric cell division entails the equal distribution of cellular components to daughter cells. However, the mechanisms governing organelle segregation remain elusive. The endoplasmic reticulum (ER), comprising perinuclear sheets and peripheral tubules in interphase, serves as a central hub for sensing cellular states and coordinating other organelle dynamics. Here, we show that upon mitotic entry, the ER undergoes reverse redistribution: tubular ER accumulates around the centrosomes, while sheet-like ER relocates to the periphery. Mechanistically, the tubular ER protein Reticulon 4 (RTN4) is phosphorylated by cyclin-dependent kinase 1 (CDK1) during early mitosis. Phosphorylation promotes the interaction between RTN4 and Rab11, leading to the dynein-dependent enrichment of RTN4 around centrosomes and consequently driving the tubularization of the pericentrosomal ER. RTN4-mediated mitotic ER reorganization ensures symmetric distribution and inheritance of the ER, further contributing to the symmetric segregation of other organelles and mitotic fidelity. Thus, our study uncovers the mechanism of ER symmetry remodeling during early mitosis and its roles in organelle inheritance and mitotic progression.
    Keywords:  Rab11 GTPase; Reticulon 4; endoplasmic reticulum; mitosis; organelle inheritance
    DOI:  https://doi.org/10.1002/advs.76193
  23. Front Immunol. 2026 ;17 1813019
    Cross-species systems analysis distinguishes inflammatory remodeling from primary mucus secretory failure in inflammatory bowel disease.
    Jessica Xhumari, Amanda Ojeda, Oluwamayowa S Akinsuyi, Luiz F W Roesch.
       Introduction: Intestinal mucus and epithelial barrier dysfunction are central features of inflammatory bowel disease (IBD), yet the regulatory mechanisms underlying mucus disruption remain inconsistent across individual studies. Anterior gradient 2 (AGR2) is an endoplasmic reticulum chaperone required for mucin folding, and its loss in mice causes primary mucus secretory failure and spontaneous colitis. Here, we integrated cross-cohort human transcriptomics with a genetic model of mucus secretory collapse to determine whether mucus dysfunction in IBD reflects intrinsic mucin-folding defects or secondary inflammatory remodeling.
    Methods: We performed a meta-analysis of 26 independent human colonic transcriptomic datasets comprising 1,302 active, untreated samples to derive a consensus mucus-barrier regulatory program in Crohn's disease (CD) and ulcerative colitis (UC). Random-effects modeling identified differentially expressed genes, which were evaluated using gene set enrichment for biological processes relevant to mucus regulation. To provide a mechanistic benchmark for primary secretory failure, we generated an orthogonal colon proteome from Agr2 -/- mice.
    Results: Across human cohorts, 3,129 genes in CD and 3,729 in UC were differentially expressed, with substantial overlap between diseases. Both conditions showed coordinated upregulation of pathways linked to goblet-cell differentiation, mucin transcription, post-translational glycosylation, secretion, microbial sensing, and endoplasmic reticulum quality control. MUC1, MUC4, MUC5AC, and MUC5B were consistently upregulated in active IBD relative to healthy controls. MUC2 was strongly elevated in CD. Glycosyltransferases, including ST3GAL1 and FUT8, were upregulated, and secretion-associated immune regulators, such as NOD2 and CASP1, increased, whereas the barrier lectin ZG16 decreased. ER stress components HSPA5, XBP1, and AGR2 were also upregulated compared with controls.
    Discussion: Cross-species comparison revealed convergence between IBD and Agr2 deficiency in unfolded-protein response and microbial sensing pathways, including lipopolysaccharide and Toll-like receptor signaling. However, cytokine-driven regulatory programs prominent in IBD, including IL-6-STAT3 and IL-17 pathways, were not recapitulated in Agr2 -/- mice. These findings indicate that mucus barrier dysfunction in human IBD reflects inflammatory remodeling of epithelial programs rather than primary secretory collapse alone, while sharing conserved ER-stress and microbial response signatures. Integrating human and murine datasets identifies candidate pathways that may stabilize mucin folding, refine glycan composition, and preserve host-microbe spatial segregation in intestinal disease.
    Keywords:  MUC2; inflammatory bowel disease (IBD); mucin; mucosal inflammation; mucus barrier dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2026.1813019
  24. Cell Death Dis. 2026 Jun 25.
    Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
    Lauren Brakefield-Laird, Amit Budhraja, Peter M Hall, Dixie Brewington, Jamila Moore, Josi Lott, Yonghui Ni, Dennis Voronin, Oliver Grant-Chapman, Tresor O Mukiza, Tristen Wright, Yong-Dong Wang, Sandi Radko-Juettner, Shondra M Pruett-Miller, Stanley Pounds, Peter Vogel, Joseph T Opferman.
      MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.
    DOI:  https://doi.org/10.1038/s41419-026-09037-w
  25. Mol Biol Cell. 2026 Jun 24. mbcE26010059
    Csf1 facilitates adaptive membrane lipid remodeling linked to ER-plasma membrane contact sites.
    Fumiyoshi Abe, Tetsuo Mioka, Yusuke Suzuki, Akane Ogasawara, Daisuke Mochizuki, Saki Imura, Yusuke Kato, Ayana Toda, Sana Nikaido, Takahiro Mochizuki.
      Membrane lipid composition must be dynamically adjusted to preserve bilayer physical properties, yet the cellular mechanisms that support bulk lipid remodeling under physical stress remain incompletely understood. Here, we identify Csf1 as a regulator of membrane lipid remodeling functionally associated with endoplasmic reticulum-plasma membrane (ER-PM) contact sites in Saccharomyces cerevisiae, with features consistent with bridge-like lipid transfer proteins. Using high hydrostatic pressure as a defined physical perturbation that constrains membrane packing, we reveal a requirement for Csf1-dependent lipid remodeling linked to ER-PM contact sites that is masked under standard growth conditions. Quantitative lipidomic and membrane biophysical analyses show that, under hydrostatic compression, loss of Csf1 disrupts coordinated lipid remodeling, leading to reduced phospholipid unsaturation, increased membrane rigidity, and destabilization of PM permeases. We further show that Csf1 cooperates with Osh6/7 to sustain lipid flux and bilayer re-equilibration linked to ER-PM contact sites under conditions permissive for Osh6/7 activity. These findings identify Csf1 as a stress-dependent lipid-remodeling factor that enables adaptive membrane remodeling and preserves membrane protein stability under conditions of constrained membrane flexibility.
    DOI:  https://doi.org/10.1091/mbc.E26-01-0059
  26. Mol Metab. 2026 Jun 25. pii: S2212-8778(26)00093-1. [Epub ahead of print] 102409
    RNASET2 degrades mRNAs that protect against lipotoxicity.
    Shuiling Zhao, Stevens Bontemps, Ryan M Nottingham, Jun Yao, Mariana Acuña, David E Cohen, Alan M Lambowitz, Jean E Schaffer.
       ABSTRACT/OBJECTIVE: RNASET2 is a lysosomal RNase whose enzymatic function is required for early events in lipotoxicity. However, the endogenous RNA substrates of RNASET2 that modulate lipid-induced cell death are not known. The purpose of this study was to identify RNASET2 substrates that impact lipotoxic stress.
    METHODS: RNA sequencing was used to identify RNAs that increase in abundance in human cells upon RNASET2 knockdown, and actinomycin D assays were used to show that RNASET2 impacted decay rates of these RNAs. We tested for the presence of these RNAs in immunoisolated lysosomes and determined the contribution of the lysosomal membrane transporter SIDT2 in delivery of these RNAs to the lysosome. A role for these RNAs in lipotoxic cell death was directly tested in loss- and gain of function analysis.
    RESULTS: RNASET2 knockdown increased steady-state abundance of UCHL3, PFN2 and PRDX3 mRNAs and prolonged their decay rate, leading to increased protein expression. These mRNAs were delivered to the lysosomal lumen by the lysosomal membrane transporter SIDT2 that mediates RNautophagy. While UCHL3 and PFN2 have not previously been implicated in lipotoxic responses, expression of these proteins protected against lipid-induced cell death.
    CONCLUSIONS: Our study identified specific mRNA substrates of RNASET2 and uncovered a previously unexplored function for lysosomes and RNautophagy in regulation of the response to metabolic stress. Moreover, we demonstrated that RNautophagy selectively regulates turnover of specific endogenous RNAs and thereby impacts regulation of gene expression.
    Keywords:  RNA degradation; autophagy; gene expression; lipotoxicity; lysosomes
    DOI:  https://doi.org/10.1016/j.molmet.2026.102409
  27. Nat Commun. 2026 Jun 22.
    Allostery is a widespread cause of loss-of-function variant pathogenicity.
    Xiaotian Liao, Ben Lehner.
      Allosteric communication between non-contacting sites in proteins plays a fundamental role in biological regulation and drug action. While allosteric gain-of-function variants are known drivers of oncogene activation, the broader importance of allostery in genetic disease and protein evolution is less clear. Here, we introduce a comparative framework that disentangles functional disruption by mutations from protein destabilization. Applying this framework across diverse datasets-ranging from paired experimental measurements of abundance and activity to proteome-wide comparisons of evolutionary fitness and biophysical stability predictions-we provide evidence that allostery is a widespread cause of loss-of-function variant pathogenicity in human genetic diseases. In addition, our analyses reveal a conserved distance-dependent decay of allosteric mutational effects outside of protein active sites. As an important mechanism of pathogenicity, allostery needs to be better mapped, understood, and predicted across the human proteome.
    DOI:  https://doi.org/10.1038/s41467-026-74517-8
  28. Mol Cell Proteomics. 2026 Jun 26. pii: S1535-9476(26)00112-X. [Epub ahead of print] 101616
    ASAP-ID: Proximity labelling with small tags.
    Ruohua Lyu, Kiersten M Ruff, Catherine S Palmer, Alejandra E Ramirez, Angelique R Ormsby, Daniel J Scott, Rohit V Pappu, Diana Stojanovski, David A Stroud, Danny M Hatters.
      Biotinylation-based proximity labelling methods are valuable for discovering protein-protein interactions within cellular systems. However, one limitation of these approaches is that most require fusing the target protein with the enzyme that biotinylates nearby proteins (i.e., TurboID or APEX2), which risks sterically disrupting the protein's native function. Here, we present a method designed to reduce the steric impact of these fusions and offer greater flexibility in labelling modalities. The method, Antibody and Small-tag Assembly on Proteins for Interaction Detection (ASAP-ID), involves a bipartite system. Target proteins are fused to a small peptide antigen that recruits TurboID or APEX2 fused to an antibody directed to the antigen. Using two different antigen/antibody systems (SunTag and MoonTag), we show that ASAP-ID can specifically label human Lamin A in cells. The method works when the target protein and nanobody are co-expressed together in cis (ASAP-IDIC). We also demonstrate that the approach works when the antibody fusion is added in trans to fixed cells post-expression (ASAP-IDIT). ASAP-IDIT identified more than 448 known and previously undescribed potential interactors of lamin. We further used ASAP-IDIT to study how ALS-mutant profilin 1 affected its interactome. The method identified proteins involved in protein quality control that correlated with aggregation propensity. Moreover, the different mutants showed variation in the cellular location where aggregates formed. ASAP-IDIT revealed preferences for mitochondrial proteins for the two profilin mutants that tend to aggregate in the cytoplasm, C71G and M114T, and nuclear proteins for a mutant more prone to nuclear aggregation. These findings position ASAP-ID as a powerful addition to the proximity labelling toolkit, capable of probing subtle differences in interactomes in a less invasive manner.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101616
  29. Nat Neurosci. 2026 Jun 26.
    The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
    Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.
      Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02320-1
  30. Int Immunopharmacol. 2026 Jun 22. pii: S1567-5769(26)00896-9. [Epub ahead of print]185 117050
    Compound BOZA attenuates fibrosis in systemic sclerosis by modulating the PERK-HNRNPA1 axis.
    Cheng Chen, Manna Lin, Jia Yu, Ji Yang.
      Endoplasmic reticulum (ER) stress is critically implicated in the pathogenesis of Systemic sclerosis (SSc), yet targeted therapeutic strategies remain limited. Here, we identify a repurposed small-molecule compound BOZA (PubChem CID: 5113653), as a potent antifibrotic agent that alleviates SSc-associated fibrosis by targeting the PERK-HNRNPA1 signaling axis. Mechanistic investigations reveal that BOZA engages the ER stress sensor PERK, suppressing its dimerization and autophosphorylation. Crucially, this inhibition blocks the ER stress-induced destabilization of the RNA-binding protein HNRNPA1. By preserving HNRNPA1 stability, BOZA modulates downstream fibrotic signaling, defining the PERK-HNRNPA1 axis as a functionally relevant regulatory node linking ER stress resolution to antifibrotic activity. Genetic rescue experiments support that BOZA's antifibrotic efficacy is significantly dependent on PERK signaling and requires HNRNPA1 stabilization. In vitro, BOZA effectively suppresses TGF-β-driven fibroblast hyperactivation, proliferation, and migration. In vivo, administration of BOZA significantly attenuates bleomycin-induced dermal and pulmonary fibrosis in mice, partially restoring tissue architecture and significantly reducing collagen deposition. Collectively, our findings identify the PERK-HNRNPA1 axis as a critical mechanism linking ER stress to fibrosis and position BOZA as a promising preclinical modulator for treating SSc.
    Keywords:  ER stress; Fibrosis; Systemic sclerosis
    DOI:  https://doi.org/10.1016/j.intimp.2026.117050
  31. Commun Biol. 2026 Jun 24.
    Adaptor-mediated interaction between Kv1.3 and Nedd4-2 E3 ubiquitin ligase.
    Irene Estadella, Anna Benavente-Garcia, Jesusa Capera, Judith Robles-Prieto, Antonio Felipe.
      The voltage-gated potassium channel Kv1.3 is crucial for immune responses. During proinflammatory stimulation, Kv1.3 is upregulated, enhancing Ca²⁺ signaling and leukocyte activation. To prevent prolonged lymphocyte activity, excess Kv1.3 must be removed from the plasma membrane, as elevated levels are linked to chronic inflammation. The ubiquitin E3 ligase Nedd4-2 is a key negative regulator that promotes Kv1.3 degradation through ubiquitination and lysosomal targeting. Because Kv1.3 lacks canonical PY motifs required for Nedd4-2 binding, adaptor proteins are necessary. Our findings show that Ndfip1 and specific 14-3-3 proteins facilitate the Nedd4-2-Kv1.3 interaction. Following PKC activation, a rapid, transient association between Kv1.3 and Nedd4-2 occurs near the membrane, initiating ubiquitination, vesicular internalization, and lysosomal degradation. This work identifies Nedd4-2 adaptors that mediate Kv1.3 regulation, highlighting Ndfip1 as a key factor while the roles of individual 14-3-3 isoforms remain to be clarified.
    DOI:  https://doi.org/10.1038/s42003-026-10557-6
  32. Mol Cell. 2026 Jun 25. pii: S1097-2765(26)00378-3. [Epub ahead of print]
    Longitudinal monitoring of cytoplasmic RBP-RNA interactions and transcriptome in living cells by engineered protein nanocages.
    Lu-Feng Hu, Gang Xie, Yi-Xia Wu, Yu-Xuan Li, Zi-Li Wan, Li Mi, Jia-Zhen Wang, Yangming Wang.
      Most existing RNA sequencing methods rely on cell lysis or fixation, limiting their use in longitudinal studies of the same cell population. Here, we introduce POND-seq (protein nanocage-empowered non-destructive sequencing), a strategy that employs secretory protein nanocages fused to RNA-binding proteins (RBPs) to recover RBP-associated RNAs from living cells. POND-seq robustly identifies RNA targets of cytoplasmic RBPs across multiple cell types and enables longitudinal tracking of dynamic changes in RBP-associated RNA profiles under stress conditions. Fusion to poly(A)-binding protein C (PABPC1) further allows monitoring of transcriptomic responses and selectively profiles cell-type-specific transcriptomes from mixed populations without cell dissociation and sorting. Additionally, POND-seq supports functional interrogation of RBP domains and residues involved in RNA association and enables scalable analysis of RBP variants, as demonstrated by a systematic assessment of disease-associated fragile X messenger ribonucleoprotein 1 (FMR1) mutations. Together, POND-seq provides a versatile and scalable platform for non-destructive and longitudinal analysis of cytoplasmic transcriptomes and RBP-associated RNAs.
    Keywords:  RBP-RNA interactions; longitudinal transcriptomics; non-destructive sequencing; protein nanocages; variant profiling
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.007
  33. EMBO J. 2026 Jun 25.
    Cellular assembly and functional resilience of the mammalian RNA exosome.
    Tsimafei Navalayeu, Nikolaus Beer, Monika Bebjaková, Robert W Kalis, Ulrich Hohmann, Karel Stejskal, Gabriela Krššáková, Nina Fasching, Veronika A Herzog, Niko Popitsch, Elisabeth Roitinger, Clemens Plaschka, Johannes Zuber, Stefan L Ameres.
      Most eukaryotic proteins assemble into multisubunit complexes that coordinate essential cellular functions, yet the principles governing their assembly and proteostatic control remain largely undefined. Here, we systematically dissect the cellular assembly and functional organization of the RNA exosome, an essential ribonucleolytic complex, using an inducible dual-guide CRISPR/Cas9 system in mouse embryonic stem cells. We reveal a sequential assembly pathway where Exosc2, Exosc4, and Exosc7 initiate complex formation, facilitating the incorporation of barrel and cap subunits in a defined hierarchy. Unlike other structural subunits, the terminally incorporated cap subunit Exosc1 is dispensable for cell viability, revealing a modular, functionally resilient architecture. We demonstrate that orphan subunits are selectively degraded via the ubiquitin-proteasome system, enforcing stringent quality control over RNA exosome biogenesis. These findings define an assembly logic of of the mammalian exosome and uncover previously unrecognized plasticity in the composition and function of this essential ribonucleolytic complex.
    DOI:  https://doi.org/10.1038/s44318-026-00824-x
  34. Nucleic Acids Res. 2026 Jun 22. pii: gkag641. [Epub ahead of print]54(12):
    ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
    Jung-Sik Joo, Mikyoung Kim, Sugyung Kim, Hyejin Kim, Hyoung-Pyo Kim.
      Endoplasmic reticulum (ER) stress triggers transcriptional programs that promote either adaptation or apoptosis, yet the epigenetic mechanisms underlying this response remain incompletely understood. Here, integrated multi-omics analyses of unfolded protein response transcription factor knockout cells identify ATF4 as a dominant regulator of ER stress-responsive enhancer activation and chromatin looping. Loss of ATF4 markedly impairs stress-induced H3K27ac accumulation and enhancer-promoter interactions at ATF4-associated regulatory elements, establishing ATF4 as a central organizer of the stress-responsive regulatory landscape. We further identify CHOP as a key functional partner of ATF4 during ER stress. Integrative analyses of ATF4 occupancy and H3K27ac landscapes in CHOP-knockout cells reveal that CHOP selectively modulates ATF4-dependent enhancer activity and controls distinct subsets of stress-responsive genes. This cooperation preferentially promotes apoptosis-associated transcriptional programs while having limited effects on core adaptive responses. Together, our findings define a hierarchical regulatory framework in which ATF4 establishes enhancer activation and chromatin looping networks, whereas CHOP selectively diversifies their output to specify ER stress-responsive gene programs.
    DOI:  https://doi.org/10.1093/nar/gkag641
  35. FEBS Lett. 2026 Jun 26.
    Mixed-class J-domain protein scaffolds promote expanded aggregate handling and multivalent Hsp70 engagement during functional disaggregase assembly.
    Anna Szlachcic, Nadinath B Nillegoda.
      Protein aggregates threaten cellular proteostasis and are linked to aging and disease. In metazoa, aggregate resolution relies on Hsp70-J-domain protein (JDP)-based disaggregases. Previous studies showed human class A and class B JDP assemblies enhance Hsp70-mediated disaggregation, but the underlying mechanism has remained unclear. Using J-domain mutants that impair Hsp70 binding while preserving mixed-class JDP interaction, we show that synergistic disaggregation is lost when either JDP partner cannot engage Hsp70. Size-resolved disaggregation assays further reveal that mixed-class JDP assemblies influence the processing of distinct luciferase aggregate populations, including aggregate species inefficiently handled by either JDP alone. Our findings support a model in which mixed-class JDP assemblies enhance Hsp70 disaggregation through expanded aggregate-processing capacity and multivalent Hsp70 recruitment by both JDP partners.
    Keywords:  disaggregase assembly; multivalent Hsp70 recruitment; primate disaggregases; substrate targeting by J‐domain protein scaffolds
    DOI:  https://doi.org/10.1002/1873-3468.70399
  36. RNA Biol. 2026 Jun 24.
    The role of RNA modifications in cancer translational control.
    Merin Joy, Alice Cleynen, Nikolay E Shirokikh.
      RNA modifications have emerged as central regulators of cancer translational control. Unlike transcriptional reprogramming, which unfolds over hours, modification-dependent translational rewiring enables rapid proteomic adaptation to the nutrient-deprived, hypoxic, and immunologically hostile tumour microenvironment. Yet most existing reviews organize epitranscriptomic mechanisms by modification type or cancer hallmark, obscuring the mechanistic logic by which chemical marks collectively reshape the translational apparatus. This review adopts a translation-centric framework, examining how the most abundant modifications on mRNAs, tRNAs, and rRNAs regulate each stage of protein synthesis in malignant cells. We survey the epitranscriptomic toolkit, including modification chemistries, enzymatic writers, readers, and erasers, and detection technologies including nanopore direct RNA sequencing. We then trace how modifications control initiation (m6A-driven mRNA circularization, cap-independent translation via eIF3 and eIF4G2, rRNA 2'-O-methylation-directed cap-to-IRES switching), elongation (m6A-induced ribosome stalling coupled to mRNA decay, tRNA mcm5s2U-mediated codon-biased translation, YTHDF1-dependent elongation factor recruitment), and termination (pseudouridine-mediated stop codon readthrough, NMD evasion). Crucially, we show that mRNA, tRNA, and rRNA modifications do not act in isolation but form integrated networks. For example, mRNA m6A and tRNA mcm5s2U operate on opposing arms of the same regulatory axis, with direct implications for therapeutic design. We assess the expanding drug pipeline, from the METTL3 inhibitor STC-15 now in Phase 1b/2 trials and METTL3-targeting PROTACs to FTO and ADAR1 inhibitors, and argue that biology-informed combination strategies targeting multiple modification axes will be essential for durable clinical responses.
    Keywords:  RNA modifications; cancer translation; epitranscriptomics; m6A; ribosome heterogeneity; translational control
    DOI:  https://doi.org/10.1080/15476286.2026.2694854
  37. J Am Chem Soc. 2026 Jun 24.
    Inhalable Polymeric PROTAC Nanococktail for Targeted Protein Degradation in Idiopathic Pulmonary Fibrosis.
    Qiaoling Tan, Yandong Zhao, Yangning Zhang, Hao Chen, Zhiqi Xu, Zhenhai Pan, Mohamed E El-Khouly, Youyong Yuan.
      Idiopathic pulmonary fibrosis (IPF) is sustained by a self-amplifying pathological circuit involving senescence-associated epithelial injury and fibroblast activation, which together drive persistent inflammatory signaling, excessive extracellular matrix deposition, and progressive loss of lung function. Although proteolysis-targeting chimeras (PROTACs) offer a powerful approach to eliminate disease-driving proteins, their application in fibrotic lung disease remains limited by inefficient pulmonary delivery, poor lesion retention, and insufficient intervention in multicellular profibrotic networks. Herein, we develop an inhalable enzyme-activated polymeric PROTAC nanococktail that enables concurrent degradation of two key profibrotic signaling regulators in fibrotic lungs. The nanococktail consists of GAL@SD and FAP@BD, two disease-microenvironment-responsive nanoparticles carrying distinct PROTAC cargos. GAL@SD responds to elevated senescence-associated β-galactosidase activity in fibrotic lungs and releases a stimulator of interferon genes (STING)-degrading PROTACs to suppress senescence-associated inflammatory signaling linked to impaired alveolar epithelial repair. FAP@BD is activated by fibroblast activation protein-α enriched in activated fibroblast-dominated fibrotic regions, delivering a bromodomain-containing protein 4 (BRD4)-degrading PROTAC to inhibit myofibroblast activation and extracellular matrix production. After inhalation, both nanoparticles exhibit efficient mucus penetration, improved pulmonary retention, and preferential accumulation in fibrotic lesions, enabling localized degradation of STING and BRD4. In a bleomycin-induced mouse model of pulmonary fibrosis, the combined PROTAC nanococktail achieves superior therapeutic efficacy compared with either single PROTAC nanoparticle, as demonstrated by restored lung architecture, improved respiratory function, reduced collagen deposition, and reversal of fibrosis-associated transcriptional programs. These results demonstrate an inhaled dual-PROTAC nanotherapeutic strategy for simultaneously attenuating epithelial senescence-associated inflammation and fibroblast-driven matrix remodeling.
    DOI:  https://doi.org/10.1021/jacs.6c09336
  38. Science. 2026 Jun 25. 392(6805): 1363-1368
    Reversible suppression of autophagy in a mouse model reveals neuronal resilience.
    Tomoya Eguchi, Manabu Abe, Takuya Tomita, Hideaki Morishita, Yasushi Saeki, Kenji Sakimura, Kenji F Tanaka, Noboru Mizushima.
      Impairments in intracellular quality-control mechanisms, including autophagy, affect neuronal integrity and function. Despite numerous studies aimed at slowing neuronal deterioration, it remains unclear whether neuronal function and intracellular quality can be restored once impaired. We developed a mouse model in which autophagy could be rapidly and reversibly regulated to investigate the reversibility of such defects. Suppressing autophagy led to proteome and transcriptome changes, inclusion body accumulation, and axonal swelling, all of which were largely ameliorated after autophagy restoration. Consistent with these cellular abnormalities, autophagy suppression induced motor and cognitive dysfunction, which was also reversed on autophagy restoration. Our findings elucidate the potential resilience of neuronal function and quality enabled by intracellular clearance.
    DOI:  https://doi.org/10.1126/science.ady3911
  39. Nat Commun. 2026 Jun 21.
    A unified platform for the rapid assembly of glutarimides for Cereblon E3 ligase modulatory drugs.
    David M Whalley, Olivier Lorthioir, Niall A Anderson, Erin Braybrooke, Susannah C Coote, Sylvain Demanze, Holly L Douglas, Okky Dwichandra Putra, Katie Proctor, Yuanyuan Si, Sam Staniland, Stephen Stokes, Alfie Woodhouse.
      Glutarimide-containing Cereblon (CRBN) ligands are critical motifs for PROTACs, molecular glue degraders and next-generation Cereblon E3 ligase modulatory drugs (CELMoDs), which represent promising therapeutic modalities in targeted protein degradation. However, the multistep synthetic routes required to access glutarimide scaffolds continue to present formidable challenges for medicinal chemists, limiting rapid structure-activity relationship (SAR) exploration and late-stage diversification. To streamline access to these privileged motifs, modular and efficient methodologies are still highly desirable. Here, we report a unified organocatalytic synthesis platform for the rapid assembly of diverse glutarimide derivatives from readily available nitrogen heterocycles. Employing a sequence of phosphine-catalysed C-N bond formation, metal-free Giese addition and acid-mediated cyclisation, this approach provides high selectivity, broad functional group tolerance and operational simplicity under conditions amenable to both multigram synthesis and high-throughput parallel synthesis. Using this platform, we rapidly prepare CRBN binder libraries, access control analogues (for example, N‑alkylated glutarimides) and perform late‑stage functionalisation of bioactive molecules. This strategy could offer a transformative solution for the efficient and cost-effective synthesis of CRBN-targeted therapeutics and chemical biology probes, overcoming longstanding synthetic bottlenecks in the field.
    DOI:  https://doi.org/10.1038/s41467-026-74673-x
  40. Mol Cell. 2026 Jun 26. pii: S1097-2765(26)00389-8. [Epub ahead of print]
    A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
    Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      How mitochondrial respiration is tightly regulated by energy demand remains incompletely defined. When mammalian cells switch from glucose to galactose as a carbon source, we observed the enhanced assembly of respiratory chain complexes accompanied by a marked reduction in TMEM141, a mitochondrial inner membrane protein. Loss of TMEM141 increased mitochondrial respiration and promoted complex I assembly, whereas galactose-induced complex I assembly was markedly blunted in TMEM141-deficient cells. TMEM141 interacts with the complex I assembly factor TIMMDC1, limiting its association with complex I subunits. TMEM141 is degraded by the mitochondrial proteases AFG3L2 and YME1L1, and galactose treatment strengthens their interactions. TMEM141 deficiency increases oxidative damage and mtDNA release, leading to activation of the cGAS-STING pathway. In Drosophila, dTMEM141 localizes to mitochondria, modulates mitochondrial activity, and is required for glial cell integrity in the eye. Together, our findings reveal TMEM141 as a negative regulator of complex I assembly that adapts to oxidative phosphorylation (OXPHOS) demands.
    Keywords:  Drosophila; OXPHOS; mitochondria; mitochondrial protease; respiration complex
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.018
  41. Nature. 2026 Jun 24.
    Alternate RNA decoding results in stable and abundant proteins in mammals.
    Shira Tsour, Rainer Machné, Andrew Leduc, Simon Widmer, Eunice Koo, Jeremy Guez, Konrad J Karczewski, Nikolai Slavov.
      Amino acid substitutions may substantially alter protein stability and function1,2. However, the contribution of substitutions that arise from alternate translation (deviations from the genetic code) is unknown. Here to address this issue, we analysed deep proteomic, transcriptomic and genomic data from more than 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,803 fragmentation spectra corresponding to 8,746 unique substitutions in proteins derived from 1,767 genes, including 1,955 confidently localized sites. Some substitutions were shared across samples, whereas others exhibited strong tissue-type and cancer specificity. Notably, products of alternate translation were more abundant than their canonical counterparts for hundreds of proteins, which suggests that there is sense-codon recoding. Recoded proteins included transcription factors, proteases, signalling proteins and proteins associated with neurodegeneration. Mechanisms that contribute to substitution abundance included protein stability, codon frequency, codon-anticodon mismatches and RNA modifications. We also characterized how alternatively translated proteoform ratios vary across protein domains, tissue types and cancers. These ratios were positively associated with intrinsically disordered regions and genetic polymorphisms in the gnomAD database, although the polymorphisms could not account for the substitutions. The sequence, relative abundance and the tissue specificity of alternatively translated proteins were conserved between humans and mice. These results demonstrate the contribution of alternate translation to the diversification of mammalian proteomes and its association with protein stability, tissue-specific proteomes and disease.
    DOI:  https://doi.org/10.1038/s41586-026-10678-2
  42. Science. 2026 Jun 25. 392(6805): eaeb3900
    Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation.
    Mårten C G Winge, Leandra V Jackrazi, Douglas F Porter, Suhas Srinivasan, Vanessa Lopez-Pajares, Dayan J Li, Benjamin Pham, Aubrey Houser, Spencer H Cha, Robin M Meyers, Lisa A Ko, Luca Ducoli, Weili Miao, Lindsey M Meservey, Brian J Zarnegar, Mark Smith, Andrew L Ji, Michael T Longaker, Paul A Khavari.
      Stratified epithelial differentiation involves transcriptional and proteomic remodeling. Here, multiomic profiling implicated ubiquitin and related posttranslational networks in differentiation dynamics. Systematic perturbation of ubiquitin-like machinery in primary human keratinocytes which uncovered opposite functions of neural-precursor-cell-expressed, developmentally down-regulated 8 (NEDD8) and small ubiquitin-related modifier 2 (SUMO2). Generation of conditional knockout mice established essential roles for NEDD8 in progenitor maintenance, skin regeneration, and inflammation, whereas SUMO2 was required for differentiation. Beyond ubiquitin-proteasome-concordant changes, NEDD8 directed proteomic regulation correlated with RNA abundance. Integration of immunoprecipitation- mass spectrometry with genome-wide suppressor screening revealed context-specific NEDDylation dependencies. Among effectors, heterogeneous nuclear ribonucleoprotein U (HNRNPU) emerged as a posttranscriptional regulator of epithelial cell state whose RNA binding repertoire was modulated by NEDDylation. Thus, NEDD8 and SUMO2 play opposite roles in epithelial homeostasis, regeneration, and inflammation, demonstrating multiple ways ubiquitin-like networks govern tissue homeostasis.
    DOI:  https://doi.org/10.1126/science.aeb3900
  43. Cancer Cell. 2026 Jun 25. pii: S1535-6108(26)00288-6. [Epub ahead of print]
    Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
    Yunhe Liu, Xiongfeng Chen, Yibo Dai, Yiyue Jia, Yann Kieffer, Luyu Xie, Zhuan Zhou, Lauren Tyler, Alex C Kim, Giulia Biffi, Akshay T Krishnamurty, Fatima Mechta-Grigoriou, Ruth Scherz-Shouval, Mara H Sherman, Shannon J Turley, Linghua Wang, Huocong Huang.
      Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.
    Keywords:  cancer-associated fibroblasts; stroma; stroma-targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.001
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