bims-proteo Biomed News
on Proteostasis
Issue of 2022–07–10
twenty papers selected by
Eric Chevet, INSERM
  1. Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
  2. Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a target of VCP/p97 and uncovers a link to HSPB1.
  3. Secretory autophagy during lysosome inhibition (SALI).
  4. SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.
  5. The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression.
  6. GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin.
  7. Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation.
  8. Transcription factor Creb3l1 maintains proteostasis in neuroendocrine cells.
  9. Role of SNAREs in Unconventional Secretion-Focus on the VAMP7-Dependent Secretion.
  10. FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity.
  11. A role for Collagen VII in matrix protein secretion.
  12. UPR Responsive Genes Manf and Xbp1 in Stroke.
  13. The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation.
  14. SQSTM1, lipid droplets and current state of their lipophagy affairs.
  15. Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression.
  16. E3 ubiquitin ligase NEURL3 promotes innate antiviral response through catalyzing K63-linked ubiquitination of IRF7.
  17. The p97 segregase cofactor Ubxn7 facilitates replisome disassembly during S-phase.
  18. TRIM24 is an insulin-responsive regulator of P-bodies.
  19. A sudden collapse: the disaggregation of amyloid fibres.
  20. Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders.
  1. EMBO J. 2022 Jul 06. e110501
    Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
    Kimberly Wolzak, Anna Nölle, Margherita Farina, Truus Em Abbink, Marjo S van der Knaap, Matthijs Verhage, Wiep Scheper.
      Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.
    Keywords:  ANG; HRI; PERK; neuron-specific; translational control
    DOI:  https://doi.org/10.15252/embj.2021110501
  2. Mol Cell. 2022 Jun 28. pii: S1097-2765(22)00577-9. [Epub ahead of print]
    Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a target of VCP/p97 and uncovers a link to HSPB1.
    Bojana Kravić, Tihana Bionda, Alexander Siebert, Pinki Gahlot, Sophie Levantovsky, Christian Behrends, Hemmo Meyer.
      Lysosomal membrane permeabilization (LMP) is an underlying feature of diverse conditions including neurodegeneration. Cells respond by extensive ubiquitylation of membrane-associated proteins for clearance of the organelle through lysophagy that is facilitated by the ubiquitin-directed AAA-ATPase VCP/p97. Here, we assessed the ubiquitylated proteome upon acute LMP and uncovered a large diversity of targets and lysophagy regulators. They include calponin-2 (CNN2) that, along with the Arp2/3 complex, translocates to damaged lysosomes and regulates actin filaments to drive phagophore formation. Importantly, CNN2 needs to be ubiquitylated during the process and removed by VCP/p97 for efficient lysophagy. Moreover, we identified the small heat shock protein HSPB1 that assists VCP/p97 in the extraction of CNN2 and show that other membrane regulators including SNAREs, PICALM, AGFG1, and ARL8B are ubiquitylated during lysophagy. Our data reveal a framework of how ubiquitylation and two effectors, VCP/p97 and HSPB1, cooperate to protect cells from the deleterious effects of LMP.
    Keywords:  AAA+ protein; HSPB1; VCP/p97; actin; autophagy; calponin; lysophagy; lysosome; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.012
  3. Autophagy. 2022 Jul 04.
    Secretory autophagy during lysosome inhibition (SALI).
    Jayanta Debnath, Andrew M Leidal.
      Both macroautophagy/autophagy and extracellular vesicle (EV) secretion pathways converge upon the endolysosome system. Although lysosome impairment leads to defects in autophagic degradation, the impact of such dysfunction on EV secretion remains poorly understood. Recently, we uncovered a novel secretory autophagy pathway that employs EVs and nanoparticles (EVPs) for the secretion of autophagy cargo receptors outside the cell when either autophagosome maturation or lysosomal function is blocked. We term this process secretory autophagy during lysosome inhibition (SALI). SALI functionally requires multiple steps in classical autophagosome formation and the small GTPase RAB27A. Because the intracellular accumulation of autophagy cargo receptors perturbs cell signaling and quality control pathways, we propose that SALI functions as a failsafe mechanism to preserve protein and cellular homeostasis when autophagic or lysosomal degradation is impaired.
    Keywords:  Autophagy cargo receptors; extracellular vesicles; lysosome; proteostasis; secretory autophagy; vesicular trafficking
    DOI:  https://doi.org/10.1080/15548627.2022.2095788
  4. Redox Biol. 2022 Jun 28. pii: S2213-2317(22)00160-4. [Epub ahead of print]54 102388
    SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.
    Ping Liu, Xi Wang, Yiwei Sun, Hongyu Zhao, Fang Cheng, Jifeng Wang, Fuquan Yang, Junjie Hu, Hong Zhang, Chih-Chen Wang, Lei Wang.
      The replication machinery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely associated with the endoplasmic reticulum (ER) in host cells. Activation of the unfolded protein response (UPR) is a strategy hijacked by coronavirus to facilitate its replication and suppress host innate immunity. Here, we have found that SARS-CoV-2 ORF8 protein accumulates in the ER and escapes the degradation system by forming mixed disulfide complexes with ER oxidoreductases. ORF8 induces the activation of three UPR pathways through targeting key UPR components, remodels ER morphology and accelerates protein trafficking. Moreover, small molecule reducing agents release ORF8 from the mixed disulfide complexes and facilitate its degradation, therefore mitigate ER stress. Our study reveals a unique mechanism by which SARS-CoV-2 ORF8 escapes degradation by host cells and regulates ER reshaping. Targeting ORF8-involved mixed disulfide complexes could be a new strategy to alleviate SARS-CoV-2 induced ER stress and related diseases.
    Keywords:  Endoplasmic reticulum; ORF8; Redox; SARS-CoV-2; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.redox.2022.102388
  5. Elife. 2022 Jul 07. pii: e71437. [Epub ahead of print]11
    The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression.
    Martín Baccino-Calace, Katharina Schmidt, Martin Müller.
      Synaptic proteins and synaptic transmission are under homeostatic control, but the relationship between these two processes remains enigmatic. Here, we systematically investigated the role of E3 ubiquitin ligases, key regulators of protein degradation-mediated proteostasis, in presynaptic homeostatic plasticity (PHP). An electrophysiology-based genetic screen of 157 E3 ligase-encoding genes at the Drosophila neuromuscular junction identified thin, an ortholog of human tripartite motif-containing 32 (TRIM32), a gene implicated in several neurological disorders, including autism spectrum disorder and schizophrenia. We demonstrate that thin functions presynaptically during rapid and sustained PHP. Presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready vesicles, largely independent of gross morphological defects. We provide genetic evidence that thin controls release through dysbindin, a schizophrenia-susceptibility gene required for PHP. Thin and Dysbindin localize in proximity within presynaptic boutons, and Thin degrades Dysbindin in vitro. Thus, the E3 ligase Thin links protein degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release.
    Keywords:  D. melanogaster; genetics; genomics; neuroscience
    DOI:  https://doi.org/10.7554/eLife.71437
  6. J Biol Chem. 2022 Jun 30. pii: S0021-9258(22)00661-5. [Epub ahead of print] 102219
    GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin.
    Erpan Ahat, Sarah Bui, Jianchao Zhang, Felipe da Veiga Leprevost, Lisa Sharkey, Whitney Reid, Alexey I Nesvizhskii, Henry L Paulson, Yanzhuang Wang.
      Recent studies demonstrated that the Golgi re-assembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease related proteins, including mutant huntingtin (Htt-Q74), SOD1, tau, and TDP43, for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55- and autophagy-dependent, and is enhanced under stress conditions such as starvation and endoplasmic reticulum (ER) stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion, and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the ER-Golgi intermediate compartment (ERGIC). Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, while inhibition of Htt-Q74 secretion by GRASP55 knockout enhances Htt aggregation and toxicity. Lastly, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including TAGLN, PAICS and PRDX1. In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington's disease.
    Keywords:  GRASP55; Golgi; aggregation; huntingtin; neurodegeneration; secretory autophagy; unconventional secretion
    DOI:  https://doi.org/10.1016/j.jbc.2022.102219
  7. Nat Commun. 2022 Jul 02. 13(1): 3812
    Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation.
    Paula P Coelho, Geoffrey G Hesketh, Annika Pedersen, Elena Kuzmin, Anne-Marie N Fortier, Emily S Bell, Colin D H Ratcliffe, Anne-Claude Gingras, Morag Park.
      Autophagy selectively targets cargo for degradation, yet mechanistic understanding remains incomplete. The ATG8-family plays key roles in autophagic cargo recruitment. Here by mapping the proximal interactome of ATG8-paralogs, LC3B and LC3C, we uncover a LC3C-Endocytic-Associated-Pathway (LEAP) that selectively recruits plasma-membrane (PM) cargo to autophagosomes. We show that LC3C localizes to peripheral endosomes and engages proteins that traffic between PM, endosomes and autophagosomes, including the SNARE-VAMP3 and ATG9, a transmembrane protein essential for autophagy. We establish that endocytic LC3C binds cargo internalized from the PM, including the Met receptor tyrosine kinase and transferrin receptor, and is necessary for their recruitment into ATG9 vesicles targeted to sites of autophagosome initiation. Structure-function analysis identified that LC3C-endocytic localization and engagement with PM-cargo requires the extended carboxy-tail unique to LC3C, the TBK1 kinase, and TBK1-phosphosites on LC3C. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signalling with autophagic degradation.
    DOI:  https://doi.org/10.1038/s41467-022-31465-3
  8. Mol Metab. 2022 Jul 05. pii: S2212-8778(22)00111-9. [Epub ahead of print] 101542
    Transcription factor Creb3l1 maintains proteostasis in neuroendocrine cells.
    Mingkwan Greenwood, Benjamin T Gillard, Rizwan Farrukh, Alex Paterson, Ferdinand Althammer, Valery Grinevich, David Murphy, Michael P Greenwood.
       OBJECTIVES: Dynamic changes to neuropeptide hormone synthesis and secretion by hypothalamic neuroendocrine cells is essential to ensure metabolic homeostasis. The specialised molecular mechanisms that allow neuroendocrine cells to synthesise and secrete vast quantities of neuropeptides remain ill defined. The objective of this study was to identify novel genes and pathways controlled by transcription factor and endoplasmic reticulum stress sensor Creb3l1 which is robustly activated in hypothalamic magnocellular neurones in response to increased demand for protein synthesis.
    METHODS: We adopted a multiomic strategy to investigate specific roles of Creb3l1 in rat magnocellular neurones. We first performed chromatin immunoprecipitation followed by genome sequencing (ChIP-seq) to identify Creb3l1 genomic targets and then integrated this data with RNA sequencing data from physiologically stimulated and Creb3l1 knockdown magnocellular neurones.
    RESULTS: The data converged on Creb3l1 targets that code for ribosomal proteins and endoplasmic reticulum proteins crucial for the maintenance of cellular proteostasis. We validated genes that compose the PERK arm of the unfolded protein response pathway including Eif2ak3, Eif2s1, Atf4 and Ddit3 as direct Creb3l1 targets. Importantly, knockdown of Creb3l1 in the hypothalamus led to a dramatic depletion in neuropeptide synthesis and secretion. The physiological outcomes from studies of paraventricular and supraoptic nuclei Creb3l1 knockdown animals were changes to food and water consumption.
    CONCLUSION: Collectively, our data identify Creb3l1 as a comprehensive controller of the PERK signalling pathway in magnocellular neurones in response to physiological stimulation. The broad regulation of neuropeptide synthesis and secretion by Creb3l1 presents a new therapeutic strategy for metabolic diseases.
    Keywords:  PERK; endoplasmic reticulum stress; hypothalamus; neuropeptide; ribosome; unfolded protein response
    DOI:  https://doi.org/10.1016/j.molmet.2022.101542
  9. Front Cell Dev Biol. 2022 ;10 884020
    Role of SNAREs in Unconventional Secretion-Focus on the VAMP7-Dependent Secretion.
    Somya Vats, Thierry Galli.
      Intracellular membrane protein trafficking is crucial for both normal cellular physiology and cell-cell communication. The conventional secretory route follows transport from the Endoplasmic reticulum (ER) to the plasma membrane via the Golgi apparatus. Alternative modes of secretion which can bypass the need for passage through the Golgi apparatus have been collectively termed as Unconventional protein secretion (UPS). UPS can comprise of cargo without a signal peptide or proteins which escape the Golgi in spite of entering the ER. UPS has been classified further depending on the mode of transport. Type I and Type II unconventional secretion are non-vesicular and non-SNARE protein dependent whereas Type III and Type IV dependent on vesicles and on SNARE proteins. In this review, we focus on the Type III UPS which involves the import of cytoplasmic proteins in membrane carriers of autophagosomal/endosomal origin and release in the extracellular space following SNARE-dependent intracellular membrane fusion. We discuss the role of vesicular SNAREs with a strong focus on VAMP7, a vesicular SNARE involved in exosome, lysosome and autophagy mediated secretion. We further extend our discussion to the role of unconventional secretion in health and disease with emphasis on cancer and neurodegeneration.
    Keywords:  SNARE; VAMP7; cancer; neurodegeneration; unconventional protein secretion
    DOI:  https://doi.org/10.3389/fcell.2022.884020
  10. Cell Metab. 2022 Jul 05. pii: S1550-4131(22)00227-3. [Epub ahead of print]34(7): 1004-1022.e8
    FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity.
    Hilde Herrema, Dongxian Guan, Jae Won Choi, Xudong Feng, Mario Andres Salazar Hernandez, Farhana Faruk, Thomas Auen, Eliza Boudett, Rongya Tao, Hyonho Chun, Umut Ozcan.
      Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.
    Keywords:  ER stress; FKBP11; NRF2; UPR signaling; glucose intolerance; insulin resistance; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2022.06.007
  11. Matrix Biol. 2022 Jun 29. pii: S0945-053X(22)00088-9. [Epub ahead of print]
    A role for Collagen VII in matrix protein secretion.
    Qingqing Cao, Grace Tartaglia, Michael Alexander, Pyung Hung Park, Shiv Poojan, Mehdi Farshchian, Ignacia Fuentes, Mei Chen, John A McGrath, Francis Palisson, Julio Salas-Alanis, Andrew P South.
      Lack of type VII collagen (C7) disrupts cellular proteostasis yet the mechanism remains undescribed. By studying the relationship between C7 and the extracellular matrix (ECM)-associated proteins thrombospondin-1 (TSP1), type XII collagen (C12) and tissue transglutaminase (TGM2) in primary human dermal fibroblasts from multiple donors with or without the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) (n=31), we demonstrate that secretion of each of these proteins is increased in the presence of C7. In dermal fibroblasts isolated from patients with RDEB, where C7 is absent or defective, association with the COPII outer coat protein SEC31 and ultimately secretion of each of these ECM-associated proteins is reduced and intracellular levels are increased. In RDEB fibroblasts, overall collagen secretion (as determined by the levels of hydroxyproline in the media) is unchanged while traffic from the ER to Golgi of TSP1, C12 and TGM2 occurs in a type I collagen (C1) dependent manner. In normal fibroblasts association of TSP1, C12 and TGM2 with the ER exit site transmembrane protein Transport ANd Golgi Organization-1 (TANGO1) as determined by proximity ligation assays, requires C7. In the absence of wild-type C7, or when ECM-associated proteins are overexpressed, C1 proximity and intracellular levels increase resulting in elevated cellular stress responses and elevated TGFβ signaling. Collectively, these data demonstrate a role for C7 in loading COPII vesicle cargo and provides a mechanism for disrupted proteostasis, elevated cellular stress and increased TGFβ signaling in patients with RDEB. Furthermore, our data point to a threshold of cargo loading that can be exceeded with increased protein levels leading to pathological outcomes in otherwise normal cells.
    Keywords:  Collagen VII; ER stress; TANGO1; and TGFβ signaling; recessive dystrophic epidermolysis bullosa; thrombospondin
    DOI:  https://doi.org/10.1016/j.matbio.2022.06.008
  12. Front Cell Neurosci. 2022 ;16 900725
    UPR Responsive Genes Manf and Xbp1 in Stroke.
    Helike Lõhelaid, Jenni E Anttila, Hock-Kean Liew, Kuan-Yin Tseng, Jaakko Teppo, Vassilis Stratoulias, Mikko Airavaara.
      Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF's function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.
    Keywords:  ARMET; CDNF; ER stress; IRE1; XBP1; mesencephalic astrocyte-derived neurotrophic factor; unfolded protein response
    DOI:  https://doi.org/10.3389/fncel.2022.900725
  13. Chem Soc Rev. 2022 Jul 06.
    The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation.
    Kristin M Riching, Elizabeth A Caine, Marjeta Urh, Danette L Daniels.
      Targeted protein degradation has exploded over the past several years due to preclinical and early clinical therapeutic success of numerous compounds, and the emergence of new degradation modalities, which has broadened the definition of what a degrader is. The most characterized and well-studied small molecule degraders are molecular glues and proteolysis targeting chimeras (PROTACs). These degraders induce a ternary complex between a target protein, degrader, and E3 ligase component, resulting in ubiquitination and subsequent degradation of the target protein via the ubiquitin proteasomal system (UPS). This event-driven process requires success at all steps through a complex cascade of events. As more systems, degraders, and targets are tested, it has become increasingly clear that achieving degradation is only the first critical milestone in a degrader development program. Rather highly efficacious degraders require a combination of multiple optimized parameters: rapid degradation, high potency, high maximal degradation (Dmax), and sustained loss of target without re-dosing. Success to meet these more rigorous goals depends upon the ability to characterize and understand the dynamic cellular degradation profiles and relate them to the underlying mechanism for any given target treated with a specific concentration of degrader. From this starting point, optimization and fine tuning of multiple kinetic parameters such as how fast degradation occurs (the rate), how much of the target is degraded (the extent), and how long the target remains degraded (the duration) can be performed. In this review we explore the diversity of cellular kinetic degradation profiles which can arise after molecular glue and PROTAC treatment and the potential implications of these varying responses. As the overall degradation kinetics are a sum of individual mechanistic steps, each with their own kinetic contributions, we discuss the ways in which changes at any one of these steps could potentially influence the resultant kinetic degradation profiles. Looking forward, we address the importance in characterizing the kinetics of target protein loss in the early stages of degrader design and how this will enable more rapid discovery of therapeutic agents to elicit desired phenotypic outcomes.
    DOI:  https://doi.org/10.1039/d2cs00339b
  14. Autophagy. 2022 Jul 07. 1-4
    SQSTM1, lipid droplets and current state of their lipophagy affairs.
    Ankit Shroff, Taras Y Nazarko.
      SQSTM1/p62 (sequestosome 1) is a well-established indicator of macroautophagic/autophagic flux. It was initially characterized as the ubiquitin-binding autophagic receptor in aggrephagy, the selective autophagy of ubiquitinated protein aggregates. Recently, several studies correlated its levels with the abundance of intracellular lipid droplets (LDs). In the absence of a bona fide receptor for the selective autophagy of LDs (lipophagy), a few studies demonstrated the role of SQSTM1 in lipophagy. Our analysis of these studies shows that SQSTM1 colocalizes with LDs, bridges them with phagophores, is co-degraded with them in the lysosomes, and affects LD abundance in a variety of cells and under diverse experimental conditions. Although only one study reported all these functions together, the overwhelming and complementary evidence from other studies suggests that the role of SQSTM1 in lipophagy via tagging, movement, aggregation/clustering and sequestration of LDs is rather a common phenomenon in mammalian cells. As ubiquitination of the LD-associated proteins under stress conditions is increasingly recognized as another common phenomenon, some other ubiquitin-binding autophagic receptors, such as NBR1 and OPTN, might soon join SQSTM1 on a list of the non-exclusive lipophagy receptors.Abbreviations: LD: lipid droplet; LIR: LC3-interacting region; PAT: Perilipin, ADRP and TIP47 domain; SAR: selective autophagy receptor.
    Keywords:  Lipid droplet; SAR; SQSTM1; lipophagy; lipophagy receptor; p62; phagophore; selective autophagy; selective autophagy receptor; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2022.2094606
  15. Front Cell Dev Biol. 2022 ;10 907423
    Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression.
    Rebeca Piatniczka Iglesia, Mariana Brandão Prado, Rodrigo Nunes Alves, Maria Isabel Melo Escobar, Camila Felix de Lima Fernandes, Ailine Cibele Dos Santos Fortes, Maria Clara da Silva Souza, Jacqueline Marcia Boccacino, Giovanni Cangiano, Samuel Ribeiro Soares, João Pedro Alves de Araújo, Deanna Marie Tiek, Anshika Goenka, Xiao Song, Jack Ryan Keady, Bo Hu, Shi Yuan Cheng, Marilene Hohmuth Lopes.
      Non-canonical secretion pathways, collectively known as unconventional protein secretion (UPS), are alternative secretory mechanisms usually associated with stress-inducing conditions. UPS allows proteins that lack a signal peptide to be secreted, avoiding the conventional endoplasmic reticulum-Golgi complex secretory pathway. Molecules that generally rely on the canonical pathway to be secreted may also use the Golgi bypass, one of the unconventional routes, to reach the extracellular space. UPS studies have been increasingly growing in the literature, including its implication in the biology of several diseases. Intercellular communication between brain tumor cells and the tumor microenvironment is orchestrated by various molecules, including canonical and non-canonical secreted proteins that modulate tumor growth, proliferation, and invasion. Adult brain tumors such as gliomas, which are aggressive and fatal cancers with a dismal prognosis, could exploit UPS mechanisms to communicate with their microenvironment. Herein, we provide functional insights into the UPS machinery in the context of tumor biology, with a particular focus on the secreted proteins by alternative routes as key regulators in the maintenance of brain tumors.
    Keywords:  ER stress; brain; cancer; glioblastoma; glioma; leaderless; secretion
    DOI:  https://doi.org/10.3389/fcell.2022.907423
  16. FASEB J. 2022 Aug;36(8): e22409
    E3 ubiquitin ligase NEURL3 promotes innate antiviral response through catalyzing K63-linked ubiquitination of IRF7.
    Fang Qi, Xin Zhang, Likun Wang, Caixia Ren, Xuyang Zhao, Jianyuan Luo, Dan Lu.
      Interferon regulatory factor 7 (IRF7), as the interferon-stimulated gene, maximally drives type I interferon (IFN) production. However, the mechanisms by which the biological function of IRF7 is regulated remain elusive. In this study, we found that IRF7 selectively interacted with the neuralized E3 ubiquitin-protein ligase 3 (NEURL3). In concomitant with IRF7 induction, NEURL3 is upregulated by NF-κB signaling in the late phase of viral infection. Moreover, NEURL3 augmented the host antiviral immune response through ubiquitinating IRF7. A mechanistic study revealed that NEURL3 triggered K63-linked poly-ubiquitination on IRF7 lysine 375, which in turn epigenetically enhanced the transcription of interferon-stimulated genes (ISGs) through disruption of the association of IRF7 with Histone Deacetylase 1 (HDAC1), consequently augmenting host antiviral immune response. Accordingly, Neurl3-/- mice produced less type I IFNs and exhibited increased susceptibility to viral infection. Taken together, our findings identify NEURL3 as an E3 ubiquitin ligase of IRF7 and shed new light on the positive regulation of IRF7 in host antiviral immune signaling.
    Keywords:  E3 ubiquitin ligase; IRF7; NEURL3; antiviral immune response; viral infection
    DOI:  https://doi.org/10.1096/fj.202200316R
  17. J Biol Chem. 2022 Jul 04. pii: S0021-9258(22)00676-7. [Epub ahead of print] 102234
    The p97 segregase cofactor Ubxn7 facilitates replisome disassembly during S-phase.
    Zeynep Tarcan, Divyasree Poovathumkadavil, Aggeliki Skagia, Agnieszka Gambus.
      Complex cellular processes are driven by the regulated assembly and disassembly of large multi-protein complexes. While we are beginning to understand the molecular mechanism for assembly of the eukaryotic DNA replication machinery (replisome), we still know relatively little about the regulation of its disassembly at replication termination. Recently, the first elements of this process have emerged, revealing that the replicative helicase, at the heart of the replisome, is polyubiquitylated prior to unloading, and that this unloading requires p97 segregase activity. Two different E3 ubiquitin ligases have now been shown to ubiquitylate the helicase under different conditions: Cul2Lrr1 and TRAIP. Here, using Xenopus laevis egg extract cell-free system and biochemical approaches, we have found two p97 cofactors, Ubxn7 and Faf1, which can interact with p97 during replisome disassembly during S-phase. We show only Ubxn7, however, facilitates efficient replisome disassembly. Ubxn7 delivers this role through its interaction via independent domains with both Cul2Lrr1 and p97 to allow coupling between Mcm7 ubiquitylation and its removal from chromatin. Our data therefore characterize Ubxn7 as the first substrate-specific p97 cofactor regulating replisome disassembly in vertebrates and a rationale for the efficacy of the Cul2Lrr1 replisome unloading pathway in unperturbed S-phase.
    Keywords:  DNA replication; Termination of DNA replication; Xenopus laevis; p97 segregase; ubiquitin
    DOI:  https://doi.org/10.1016/j.jbc.2022.102234
  18. Nat Commun. 2022 Jul 08. 13(1): 3972
    TRIM24 is an insulin-responsive regulator of P-bodies.
    Wen Wei, Qiaoli Chen, Minjun Liu, Yang Sheng, Qian OuYang, Weikuan Feng, Xinyu Yang, Longfei Ding, Shu Su, Jingzi Zhang, Lei Fang, Antonio Vidal-Puig, Hong-Yu Wang, Shuai Chen.
      Insulin is a potent inducer of mRNA transcription and translation, contributing to metabolic regulation. Insulin has also been suggested to regulate mRNA stability through the processing body (P-body) molecular machinery. However, whether and how insulin regulates mRNA stability via P-bodies is not clear. Here we show that the E3-ligase TRIM24 is a critical factor linking insulin signalling to P-bodies. Upon insulin stimulation, protein kinase B (PKB, also known as Akt) phosphorylates TRIM24 and stimulates its shuttling from the nucleus into the cytoplasm. TRIM24 interacts with several critical components of P-bodies in the cytoplasm, promoting their polyubiquitylation, which consequently stabilises Pparγ mRNA. Inactivation of TRIM24 E3-ligase activity or prevention of its phosphorylation via knockin mutations in mice promotes hepatic Pparγ degradation via P-bodies. Consequently, both knockin mutations alleviate hepatosteatosis in mice fed on a high-fat diet. Our results demonstrate the critical role of TRIM24 in linking insulin signalling to P-bodies and have therapeutic implications for the treatment of hepatosteatosis.
    DOI:  https://doi.org/10.1038/s41467-022-31735-0
  19. EMBO J. 2022 Jul 05. e111700
    A sudden collapse: the disaggregation of amyloid fibres.
    Suzanne Couzijn, Ellen Aa Nollen.
      A hallmark of age-related neurodegenerative diseases is the presence of highly stable protein aggregates, also known as amyloid fibres. As these fibres are strongly associated with disease, it is thought that clearance of these fibres could delay or prevent disease progression. In this issue of The EMBO Journal, Beton et al unravel how the Hsc70/DNAJB1/Apg2 disaggregase machinery disassembles amyloid fibres, using α-synuclein fibrils implicated in Parkinson's Disease as a model substrate.
    DOI:  https://doi.org/10.15252/embj.2022111700
  20. Chem Soc Rev. 2022 Jul 07.
    Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders.
    Junichi Yamamoto, Takumi Ito, Yuki Yamaguchi, Hiroshi Handa.
      Progress in strategies aimed at breaking down therapeutic target proteins has led to a paradigm shift in drug discovery. Thalidomide and its derivatives are the only protein degraders currently used in clinical practice. Our understanding of the molecular mechanism of action of thalidomide and its derivatives has advanced dramatically since the identification of cereblon (CRBN) as their direct target. The binding of thalidomide derivatives to CRBN, a substrate recognition receptor for Cullin 4 RING E3 ubiquitin ligase (CRL4), induces the recruitment of non-native substrates to CRL4CRBN and their subsequent degradation. This discovery was a breakthrough in the current rapid development of protein-degrading agents because clarification of the mechanism of action of thalidomide derivatives has demonstrated the clinical value of these compounds. This review provides an overview of the mechanism of action of thalidomide and its derivatives and describes perspectives for protein degraders.
    DOI:  https://doi.org/10.1039/d2cs00116k
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