bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–04–05
sixteen papers selected by
William Grey, University of York
  1. Hematopoietic Stem Cell Senescence and Opportunities for Intervention.
  2. Long-term clonal analysis using stochastic models reveals heterogeneity and quiescence of hematopoietic stem cells.
  3. Trisomy 8 alters chromatin conformations and activates Y chromosome genes in stem cells to drive a pre-leukemic state.
  4. Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.
  5. Targeting LAPTM5 enhances AML sensitivity to cytarabine through autophagy inhibition.
  6. Spatial multi-omics of multiple myeloma uncovers niche-dependent pro-myeloma and immunosuppressive signaling in the bone marrow and extramedullary lesions.
  7. The "Sweet" crosstalk between refractory leukemia cells and vascular niche.
  8. Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D immunotherapy.
  9. Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
  10. IL-6-driven POU2AF1 and ELL2 are key regulators of multiple myeloma-distinct transcriptional and splicing programs.
  11. A neuropeptide regulates cell non-autonomous protein homeostasis.
  12. Therapeutic inhibition of myeloperoxidase with AZD5904 attenuates disease progression in mouse models of early-stage and relapsed multiple myeloma.
  13. Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
  14. Deconstructing senescence phenotypes in cells of the bone and bone marrow.
  15. Vascular smooth muscle RbFox2 regulates the cytoskeleton and arterial stiffness by a RhoBTB1-Cullin-3 mechanism.
  16. Ndfip2 in TrkA-expressing sensory neurons regulates noxious mechanosensation through control of TrkA signaling and protein levels.
  1. Exp Hematol. 2026 Mar 30. pii: S0301-472X(26)00058-5. [Epub ahead of print] 105425
    Hematopoietic Stem Cell Senescence and Opportunities for Intervention.
    Aditya Barve, Preeti Dabas, Terri Cain, Shannon McKinney-Freeman.
      How the cellular state of senescence manifests in hematopoietic stem cells (HSCs) is currently poorly understood and likely orchestrated by a complex interplay of intrinsic and extrinsic factors, such as genetic instability, epigenetic reprograming, alterations in the stem cell niche and metabolic dysregulation. Accumulating senescence may contribute to the age-related functional decline of HSCs, which manifests as reduced self-renewal, impaired differentiation, altered hematopoietic regenerative potential, expansion of dysfunctional HSC clones, and increased susceptibility to hematological disorders. Recent work has advanced our understanding of the molecular hallmarks and signaling pathways that contribute to HSC senescence, nominating promising therapeutic targets to ameliorate age-associated hematopoietic dysfunction and malignancy. Here, we review the intrinsic and extrinsic factors that likely contribute to HSC senescence during homeostasis and pathological conditions. We further summarize senescence targeting strategies that may be leveraged to mitigate HSC senescence and restore hematopoietic function during aging or hematologic disease.
    DOI:  https://doi.org/10.1016/j.exphem.2026.105425
  2. Comput Biol Med. 2026 Mar 31. pii: S0010-4825(26)00213-1. [Epub ahead of print]208 111650
    Long-term clonal analysis using stochastic models reveals heterogeneity and quiescence of hematopoietic stem cells.
    Yuri Garcia Vilela, Lars Thielecke, Artur C Fassoni, Ingmar Glauche.
      Hematopoietic stem cells (HSCs) maintain lifelong production of blood by balancing self-renewal and differentiation. However, certain aspects of their divisional dynamics, namely the role of quiescence and the intrinsic heterogeneity of the HSC pool, are not completely understood. High-resolution clonal tracking provides a powerful resource to investigate such dynamics as the data captures patterns of clonal persistence, dilution and late clonal emergence. Here, we apply mechanistic mathematical modeling to longitudinal clonal data from non-human primates to explore structural requirements that underlie the observed dynamical patterns. We show that models treating HSCs as a single, homogeneous population can explain the gradual loss of clonal diversity, but fail to reproduce clone size distributions and the long-term persistence of small and late-appearing clones. To address this, we propose a stochastic, two-compartment model in which HSCs transition reversibly between an actively cycling state and a quiescent, potentially niche-bound state. Compared to the simpler one-compartment model, this advanced framework provides a substantially improved fit for different metrics, consistently captures clone size distributions and explains the delayed activation and sustained coexistence of small and large clones. These results provide quantitative evidence that heterogeneity within the HSC pool, particularly the existence of a reversible quiescent state, is critical to account for clonal aspects of long-term hematopoiesis. Our findings highlight how clonal data can uncover underlying regulatory mechanisms and supports a central role for niche-mediated HSC quiescence in maintaining stable and diverse blood production over time.
    Keywords:  Clonal tracking; Hematopoietic stem cells; Quiescence; Stochastic modeling
    DOI:  https://doi.org/10.1016/j.compbiomed.2026.111650
  3. Oncogene. 2026 Apr 04.
    Trisomy 8 alters chromatin conformations and activates Y chromosome genes in stem cells to drive a pre-leukemic state.
    Jie Bai, Kimi Araki, Daisuke Kurotaki, Eerdunduleng, Supannika Sorin, Kei Hiramatsu, Narumi Uno, Ai Hamashima, Mihoko Iimori, Kenta Kikuchi, Minoru Terashima, Sho Kubota, Kensaku Kohrogi, Gang Huang, Minetaro Ogawa, Mitsuo Oshimura, Yasuhiro Kazuki, Goro Sashida.
      The mechanistic role of trisomy 8 in the development of myelodysplastic syndrome (MDS) remains poorly defined. Here, we generated a trisomy 8 mouse model by transferring a human chromosome 8 into murine embryonic stem cells and prospectively examined the effects on hematopoietic stem cells (HSC) by trisomy 8. The expression of inflammatory genes was enhanced, and hematopoietic programs mediated by transcription factors and polycomb repressive complex 2 (PRC2) were dysregulated in trisomy 8 HSC, which impaired their self-renewal and balanced differentiation. Trisomy 8 HSC altered the chromatin accessibility and conformations and activated Y chromosome genes, such as Uty/Kdm6c epigenetic modifier, which is known to demethylate histone H3K27me3 modification. The Uty gene facilitated the activation of PRC2-target and Runx1-target genes in leukemogenesis and drove the proliferation of human trisomy 8 leukemic cells. Since the RUNX1 gene is frequently mutated in patients with trisomy 8 MDS, its deletion attenuated the enhanced expression of inflammatory genes and mitigated the impaired self-renewal of trisomy 8 HSC in mice. Our findings reveal that trisomy 8 altered the transcriptional programs and chromatin conformations in HSC and drove a pre-malignant state through activating the expression of Uty, suggesting a route for the development of trisomy 8 MDS.
    DOI:  https://doi.org/10.1038/s41388-026-03763-3
  4. Haematologica. 2026 Apr 02.
    Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.
    Upendarrao Golla, Riya Bhalodia, Charyguly Annageldiyev, Satyam Patel, Vishnu Sravan Bollu, Su-Fern Tan, Myles C Cabot, David J Feith, Thomas P Loughran, Ross L Levine, Shin Mineishi, Hong Zheng, Kentaro Minagawa, Jeremy Hengst, Giselle L Saulnier Sholler, Dhimant Desai, Sinisa Dovat, Kelsey H Fisher-Wellman, David F Claxton, Arati Sharma.
      Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy requiring concomitant targeting of critical cellular survival pathways due to resistance and frequent relapse with monotherapies. Venetoclax (VEN), a BCL-2 inhibitor, is one such promising clinical agent best utilized in combination therapies due to transient responses and acquired resistance. Given the involvement of the Rho/ROCK pathway in VEN activity, we combined Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKi))with VEN to achieve superior antileukemic activity. The ROCKi (Fasudil, DJ4, GSK269962A) synergized with VEN to enhance cytotoxicity in both VEN-sensitive and VEN-resistant cell lines in vitro. Among the three ROCKi, GSK269962A (GSK) was best-tolerated in combination with VEN and effectively inhibited leukemia growth across multiple AML cell line-derived xenograft models in vivo. The GSK+VEN combination exhibited additive to synergistic cytotoxicity in primary AML patient cells ex vivo and enhanced antileukemic activity in a patientderived xenograft model. Additionally, the GSK+VEN combination significantly decreased the clonogenicity of primary AML cells, relatively sparing normal cells. Functional assays demonstrated enhanced apoptosis (Annexin V, caspase-3/7), elevated reactive oxygen species, and mitochondrial depolarization in both VENsensitive and VEN-resistant AML cells following combination treatment. Mechanistically, GSK augmented venetoclax responses by downregulating anti-apoptotic proteins (BCL2, MCL1) and inducing pro-apoptotic mediators (NOXA, MCL1 short isoforms), including in VEN-resistant AML cells. Together, these findings across multiple preclinical AML models demonstrate synergistic antileukemic activity and support combining VEN with ROCKi as a promising therapeutic strategy for AML.
    DOI:  https://doi.org/10.3324/haematol.2025.289041
  5. Cell Death Dis. 2026 Mar 30.
    Targeting LAPTM5 enhances AML sensitivity to cytarabine through autophagy inhibition.
    Yuqing Zeng, Chao He, Hongbo Chen, Fang Cheng.
      Upregulation of autophagy in acute myeloid leukemia (AML) cells contributes to the development of resistance to cytarabine (AraC). LAPTM5 is mainly expressed in hematopoietic and immune cells, and has been associated with the progression of multiple cancers; however, its role in AML drug resistance remains uncharacterized. Here, we reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from AML patients and found distinct gene expression profiles between AraC-resistant AML cells and untreated controls. Differentially expressed genes were significantly enriched in lysosome-related pathways, with LAPTM5 being highly expressed in drug-resistant cells, suggesting that it may be a key mediator of AraC resistance in AML. Mechanistically, AraC-resistant cells exhibited enhanced autophagic flux supported by LAPTM5-mediated upregulation of LAMP1 and LAMP2. Conversely, LAPTM5 knockdown impaired autophagolysosome formation by disrupting lysosomal biogenesis, thereby sensitizing resistant cells to AraC. These findings indicate that targeting LAPTM5 could enhance AraC sensitivity in AML by modulating autophagy. In vivo experiments further confirmed that the depletion of LAPTM5 inhibited tumor growth and synergistically suppressed AML progression with AraC. Collectively, our study identifies LAPTM5 as a critical regulator of AraC resistance via autophagy modulation, highlighting its potential as a therapeutic target for AML.In AML, AraC treatment induces LAPTM5 upregulation, which promotes LAMP1/2 transcription and lysosomal biogenesis. This facilitates autophagolysosome formation and enhances autophagic flux to reduce AraC-induced apoptosis, resulting in drug resistance. Targeting LAPTM5 represents a promising strategy to overcome this autophagy-mediated resistance.
    DOI:  https://doi.org/10.1038/s41419-026-08654-9
  6. bioRxiv. 2026 Mar 25. pii: 2026.03.23.713195. [Epub ahead of print]
    Spatial multi-omics of multiple myeloma uncovers niche-dependent pro-myeloma and immunosuppressive signaling in the bone marrow and extramedullary lesions.
    Denis J Ohlstrom, Marina E Michaud, Mojtaba Bakhtiari, Junia Vieira Dos Santos, William C Pilcher, Alden Staub, Sarthak Satpathy, Katherine Ferguson, Sowmitri Mantrala, Seunghee Kim-Schulze, Zhihong Chen, Sagar Lonial, Melissa L Kemp, Daniel Sherbenou, Alessandro Lagana, David L Jaye, Ajay K Nooka, Samir Parekh, Manoj K Bhasin.
      Multiple myeloma (MM) is a plasma cell malignancy shaped by dynamic interactions between MM cells and non-malignant cells in the immune microenvironment. To spatially profile the influence of cellular context on MM and immune cell expression, we developed a multimodal framework integrating 10x Genomics Visium HD, 10x Genomics Xenium, and clinically annotated single-cell RNA (scRNA-seq) sequencing datasets. Visium HD enabled unbiased, whole transcriptome, spatial discovery at 16 µm resolution, Xenium provided orthogonal validation at single-cell resolution, and scRNA-seq extended findings by mapping spatial labels and leveraging the greater sequencing depth. We developed a custom framework for cell type annotation within Visium HD spatial bins. Our approach enabled identification of plasma cell-dense niches enriched for non-canonical Wnt signaling, associated with gene expression supporting cell adhesion mediated drug resistance, inferior progression-free survival, and extramedullary lesions. Immune cells within these neighborhoods exhibited suppressed transcriptional states, including increased inhibitory receptor expression such as LAG3 . Utilizing the niche-driven transcriptional states in MM and immune cells, we were able to develop a 15-gene signature independently predictive of progression free survival (HR = 2.00, p < 0.0001). Collectively, this study demonstrates the potential of integrated spatial and single-cell transcriptomics to define niche-specific programs supporting MM progression.
    DOI:  https://doi.org/10.64898/2026.03.23.713195
  7. Haematologica. 2026 Apr 02.
    The "Sweet" crosstalk between refractory leukemia cells and vascular niche.
    Hui Cheng.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300820
  8. Leukemia. 2026 Mar 31.
    Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D immunotherapy.
    Umair Munawar, Johanna Thurner, Silvia Nerreter, Thomas Nerreter, Alexander M Leipold, Seungbin Han, Christina Verbruggen, Elena Gerhard-Hartmann, Cornelia Vogt, Björn Grams, Shilpa Kurian, Emma Besant, Sabine Roth, Julia Weingart, Patrick Eiring, Marietta Truger, Nazia Afrin, Torsten Steinbrunn, Yoko Tamamushi, Xiang Zhou, Nina Rein, Johanna Lehmann, Max Köppel, Andreas Rosenwald, Claudia Haferlach, Michael Hudecek, Antoine-Emmanuel Saliba, Leo Rasche, Markus Sauer, Hermann Einsele, Bernhard Kuster, Johannes Waldschmidt, K Martin Kortüm.
      Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target. Monoallelic loss of GPRC5D is frequently observed in newly diagnosed MM patients, and the incidence of acquired GPRC5D alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline monoallelic and therapy-induced biallelic GPRC5D alterations remain poorly understood. In this study, we modeled monoallelic versus biallelic loss of GPRC5D to investigate their impact on MM cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that monoallelic GPRC5D loss in OPM-2 cells reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of GPRC5D alters the transcriptional state of MM cells and promotes reprogramming of the phosphoproteomic circuitry ultimately resulting in a pro-proliferative chemokine environment. As a result, GPRC5D deficiency increases the basal proliferation rate of MM cells thereby providing a competitive advantage which may further be amplified by selecting these aggressive phenotypes during ongoing treatment with anti-GPRC5D immunotherapies.
    DOI:  https://doi.org/10.1038/s41375-026-02920-7
  9. Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00263-9. [Epub ahead of print]45(4): 117185
    Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
    Léa Goupille, Alexandre Boudet, Laura Lauture, Ambrine Sahal, Guillaume Gautier-Renard, Emeline Chu-Van, Anvi Laetitia Nguyen, Céline Chollet, Coralie Alcazar, Isabelle Bernard, François Vergez, Véronique de Mas, Christian Récher, Tony Kaoma, Paolo Gallipoli, Vilma Dembitz, Irene Basili, Flavia Bernardi, Olivier Ayrault, Carine Joffre, Florence Castelli, Benoit Colsch, Nathalie Bourgès-Abella, Fanny Granat, Jean-Emmanuel Sarry.
      FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with adverse prognosis. FLT3 inhibitors (FLT3i) improve therapeutic response; however, diverse resistance mechanisms, such as adaptations in lipid metabolism, have been identified. We hypothesized that a lipid-rich ketogenic diet (KD) might alter both host and tumoral lipid metabolism, enhancing responses to FLT3i. In FLT3-mutated AML mouse models, 3 weeks of lard- or plant-based KD improved the efficacy of FLT3i by 2-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver, and AML cells and also induced a polyunsaturated fatty acid:monounsaturated fatty acid (PUFA:MUFA) imbalance. KD impacted pentoses, hexoses, and amino acid metabolism, enhancing sugar phosphates and vitamins in the host. Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.
    Keywords:  CP: cancer; CP: metabolism; FLT3-ITD mutations; acute myeloid leukemia; ketogenic diet; metabolism; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2026.117185
  10. Blood Adv. 2026 Apr 02. pii: bloodadvances.2025018710. [Epub ahead of print]
    IL-6-driven POU2AF1 and ELL2 are key regulators of multiple myeloma-distinct transcriptional and splicing programs.
    Yasuyo Ohguchi, Masahiko Ajiro, Daisuke Ogiya, Takeshi Masuda, Yawara Kawano, Shingo Usuki, Tomoaki Koga, Shinjiro Hino, Takeshi Harada, Satoru Takahashi, Seiji Okada, Jun-Ichirou Yasunaga, Goro Sashida, Sumio Ohtsuki, Mitsuyoshi Nakao, Takashi Minami, Akihide Yoshimi, Hiroto Ohguchi.
      Multiple myeloma (MM) is a plasma cell neoplasm that depends on the bone marrow (BM) microenvironment; however, the underlying mechanisms of epigenetic contribution to the pathogenesis of MM are incompletely understood. Here, we delineate the epigenetic-driven transcriptional and splicing regulation crucial for MM. We recharacterized transcriptional program induced by IL-6/JAK/STAT3 pathway by integrating ChIP-seq, transcriptomic analyses, and CRISPR knockout screening results, and identified B cell lineage factors, POU2AF1 and ELL2, as crucial IL-6/JAK/STAT3 targets essential for MM cell growth and survival. Genetic depletion of these factors significantly suppressed MM cell growth in vitro and in the xenograft model of IL-6 humanized mice. Mechanistically, POU2AF1 and ELL2 form an autoregulatory loop with IRF4 and establish MM-distinct transcriptional program representing immaturity, and IL-6/JAK/STAT3 pathway augments this program through upregulating and recruiting these factors to the MM-signature genes. Furthermore, POU2AF1 and ELL2 are essential in the regulation of IL-6-dependent alternative RNA splicing. Immunocytochemical and proteomic analyses revealed that POU2AF1 colocalizes and facilitates formation of nuclear speckles, where it interacts with multiple trans-acting splicing factors required for MM cell growth. These findings suggest the dual roles of POU2AF1 and ELL2 in coordinating transcription and RNA splicing to generate MM-associated mRNA isoforms. Finally, we showed that gapmer antisense oligonucleotides targeting POU2AF1 inhibit its expression and MM cell growth in the presence of soluble BM stromal cell factors, including IL-6. Our data demonstrate that IL-6-driven B cell-lineage factors are the vulnerability of MM cells and may represent novel therapeutic targets for this incurable tumor.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018710
  11. Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00285-8. [Epub ahead of print]45(4): 117207
    A neuropeptide regulates cell non-autonomous protein homeostasis.
    Carrie A Sheeler, Jacqueline Y Lo, Areebah Rahman, Saebom Kwon, Daviana Menendez Escalera, Emmett Griffin-Baldwin, Karmen Mah, Adam Roszczyk, Jennifer L Garrison, Ashley E Frakes.
      The coordination of proteostasis between the brain and peripheral tissues is essential for the health and survival of all animals. In C. elegans, glia coordinate organismal proteostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the signaling molecules required remain unknown. Here, we show that glial UPRER activation increases levels of specific neuropeptides. We identify a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER and protect against chronic ER stress. FLP-17 signals partially through the receptor, EGL-6, to activate transcellular UPRER and confer stress resistance. Both XBP-1 and PERK are required for maximal FLP-17-induced UPRER activation, though only XBP-1 is necessary for organismal ER stress resistance. This work reveals a complex neuropeptide network initiated by glial UPRER activation and identifies FLP-17 as a critical mediator that coopts an existing sensory-metabolic circuit to coordinate organismal proteostasis.
    Keywords:  C. elegans; CP: cell biology; ER stress; cell non-autonomous cellular signaling; cellular stress responses; endoplasmic reticulum; glia; neurons; neuropeptides; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117207
  12. Haematologica. 2026 Apr 02.
    Therapeutic inhibition of myeloperoxidase with AZD5904 attenuates disease progression in mouse models of early-stage and relapsed multiple myeloma.
    Connor M D Williams, Jacqueline E Noll, Dylan Harnas, Hayley B Parkinson, Duncan R Hewett, Andrew C W Zannettino, Kate Vandyke, Thomas R Cox, Vasilios Panagopoulos.
      Despite advances in therapeutic strategies for multiple myeloma (MM), long-term outcomes remain poor, largely due to inevitable relapse and acquired drug resistance. Reciprocal interactions between malignant MM plasma cells (PCs) and the bone marrow microenvironment (BMME) drive disease progression, immune evasion, and therapeutic resistance, positioning the BM niche as a focus for targeted therapeutics. Myeloperoxidase (MPO) has recently emerged as a key regulator of MM progression via modification of the BMME. Here, we evaluate the efficacy of AZD5904, an orally bioavailable, irreversible MPO inhibitor, in preclinical models of MM. Initiation of MPO inhibition with AZD5904 during the early stages of MM tumour development significantly reduced tumour burden in the KaLwRij/5TGM1 and Vk*Myc murine models, however had no effect when initiated in established disease. Furthermore, AZD5904 modulated immune responses by decreasing PD1+ T cells in vivo and restoring CD8+ T cell cytotoxicity in vitro. While combining AZD5904 with the frontline agent bortezomib did not provide additional benefit in limiting disease progression, adjuvant AZD5904 following bortezomib treatment markedly delayed 5TGM1 tumour relapse. These findings suggest that while MPO inhibition may not enhance efficacy of bortezomib induction therapy, it holds promise as a maintenance strategy to improve long-term outcomes in MM. Collectively, our data support further investigation of AZD5904 as a novel maintenance therapy targeting the BM microenvironment, with potential to enhance and sustain the effectiveness of existing, standard of care regimens.
    DOI:  https://doi.org/10.3324/haematol.2025.300383
  13. bioRxiv. 2026 Mar 28. pii: 2026.03.27.714830. [Epub ahead of print]
    Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
    Guy B Kunzmann, William E Leiter, Sophie E Durn, Amy M Weeks, Jason R Cantor.
      Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein (UBL) covalently attached to substrates through a dedicated enzymatic cascade (UFMylation) and removed by specific proteases. Despite a key role in endoplasmic reticulum (ER)-ribosome homeostasis, the basis by which this UBL supports cell fitness remains elusive, as the essentiality of UFMylation machinery varies widely across hundreds of cancer lines. Here, we trace a conditional dependence on the UFMylation pathway to the availability of alanine, an amino acid provided by human plasma-like medium but absent from most conventional synthetic media. We show that by facilitating the clearance of stalled ribosomes at the ER, dynamic UFMylation maintains cellular levels of glutamic-pyruvic transaminase 2 (GPT2), the primary enzyme responsible for de novo alanine synthesis in most human cancer lines. This buffering preserves the alanine pools required to sustain protein synthesis under alanine-restricted conditions. Beyond GPT2, UFM1 deficiency leads to widespread proteomic remodeling that spans diverse processes, including mitochondrial translation. Our results reveal that despite primarily targeting ER-localized ribosomes, the UFMylation system orchestrates a multi-organelle proteostasis network whose client composition and contributions to cell fitness are shaped by intrinsic factors and nutrient conditions.
    DOI:  https://doi.org/10.64898/2026.03.27.714830
  14. J Clin Invest. 2026 Apr 01. pii: e204645. [Epub ahead of print]136(7):
    Deconstructing senescence phenotypes in cells of the bone and bone marrow.
    Lorenz C Hofbauer, Martina Rauner.
      Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.
    DOI:  https://doi.org/10.1172/JCI204645
  15. JCI Insight. 2026 Apr 02. pii: e202638. [Epub ahead of print]
    Vascular smooth muscle RbFox2 regulates the cytoskeleton and arterial stiffness by a RhoBTB1-Cullin-3 mechanism.
    Gaurav Kumar, Nisita Chaihongsa, Daniel T Brozoski, Daria Golosova, Ibrahim Vazirabad, Ko-Ting Lu, Kelsey K Wackman, Ravi K Singh, Curt D Sigmund.
      The RhoBTB1-Cullin3 (CUL3) pathway in smooth muscle cells (SMCs) controls the ubiquitination and proteasomal degradation of target proteins that regulate vasodilation, vasoconstriction, and the actin cytoskeleton, and through this blood pressure (BP) and arterial stiffness. Using proximity labelling coupled with mass spectrometry in A7R5 SMCs, we identified proteins which bound to the C-terminal half of RhoBTB1 which functions as an adapter to deliver substrates to CUL3. We examined the physiological relevance of one of these substrates, RbFox2. Co-immunoprecipitation validated the interaction of RbFox2 with RhoBTB1. RbFox2 expression was elevated in response to inhibition of the ubiquitination-proteasomal pathway, CUL3-deficiency, and RhoBTB1 inhibition by either siRNA or angiotensin II (ANG). RbFox2 was ubiquitinated in a RhoBTB1- and CUL3-dependent manner suggesting its regulation through the RhoBTB1-CUL3-dependent ubiquitin-proteasome pathway. Inhibition of RbFox2 impaired the actin cytoskeleton in A7R5 cells and in primary SMC from RbFox2Flox/Flox (RbFox2F/F) mice and decreased the levels of globular and filamentous actin. ANG increased BP and arterial stiffness of RbFox2F/F mice, but the progression of arterial stiffness was halted after SMC-specific RbFox2 deletion despite a continued rise in BP. We conclude that RhoBTB1 and RbFox2 are important regulators of arterial stiffness through a mechanism that influences cytoskeletal integrity.
    Keywords:  Cardiology; Hypertension; Mouse models; Proteomics; Vascular biology
    DOI:  https://doi.org/10.1172/jci.insight.202638
  16. Cell Death Dis. 2026 Mar 31.
    Ndfip2 in TrkA-expressing sensory neurons regulates noxious mechanosensation through control of TrkA signaling and protein levels.
    Daniel Cañada-García, Ana Hernández-García, Cristina Vicente-García, Jorge Valero, Maurilyn Ayon-Olivas, Sharad Kumar, Michael Sendtner, Juan Carlos Arévalo.
      Nociception, the neural process underlying pain detection, is modulated by the NGF/TrkA signaling axis. Although anti-NGF antibodies can alleviate chronic pain, their clinical application is limited by adverse effects, underscoring the need to identify downstream regulators of this pathway. One such mechanism involves TrkA ubiquitination mediated by Nedd4 E3 ubiquitin ligases, whose activity is modulated by Nedd4 family interacting protein 2 (Ndfip2). Notably, Ndfip2 expression is regulated by TrkA signaling under pain conditions. Here, we characterize the physiological and molecular roles of Ndfip2 in sensory neurons. We demonstrate that Ndfip2 localizes to the endoplasmic reticulum and Golgi apparatus and interacts with TrkA in sensory neurons. Conditional deletion of Ndfip2 in TrkA-expressing cells selectively alters mechanical nociception. Mechanistically, loss of Ndfip2 decreases total TrkA protein levels, downstream activation, and cell-surface exposition, particularly in male-derived dorsal root ganglia neurons. Conversely, Ndfip2 expression reduces mature glycosylated TrkA and promotes the accumulation of non-glycosylated forms, consistent with impaired receptor maturation. Together, these findings identify Ndfip2 as a post-translational regulator of TrkA in TrkA-lineage sensory neurons and establish its in vivo role in mechanical nociception.
    DOI:  https://doi.org/10.1038/s41419-026-08670-9
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