Journal of Biological Chemistry最新文献

{"title":"Sal is a proteobacterial bile acid aldolase that repurposes key thiolase catalytic residues for retroaldol cleavage of C₅ steroid side chains.","authors":"Nicolas Rolfe, Kurt L Schroeter, Taylor Jb Forrester, Matthew S Kimber, Stephen Yk Seah","doi":"10.1016/j.jbc.2025.110439","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110439","url":null,"abstract":"<p><p>Aldolases hold potential as biocatalysts for synthesis of novel steroid pharmaceuticals. The steroid aldolase from Comamonas testosteroni (CtSal) forms a complex with C. testosteroni steroid hydratase (CtShy). CtSal cleaves the C₅ side chain of bile acid thioester steroids, whereas a previously characterized actinobacterial homolog from Thermonospora curvata (TcLtp2) targets the C₃ side chain. We identified Tyr302 and Cys304 as the catalytic residues in CtSal, different from the paired Tyr residues found in TcLtp2. The 1.95 Å structure of CtSal bound to the C-terminal domain of unknown function 35 (DUF35) of CtShy (CtShy_DUF35-CtSal) reveals a central CtSal dimer flanked by two CtShy_DUF35 domains in an αββα arrangement. CtShy_DUF35 has a unique Cys₃His₁ (C₃H₁) zinc finger that shapes the substrate-binding cleft of CtSal, preventing the binding of the flat cholesterol rings while accommodating the bent rings of bile acids. Phylogenetically, Sals and Ltp2s form separate clades and are distantly related to thiolases. Intriguingly, a Trypanosoma brucei homolog, annotated as a thiolase-like protein (TbSLP), shares catalytic architecture of CtSal, suggesting an aldolase rather than a thiolase function. This study provides the first detailed characterization of a C₅ side chain steroid aldolase, revealing its unique catalytic features and expanding our understanding of steroid side chain catabolism in Proteobacteria.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110439"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GAPDH heme delivery to Indoleamine 2,3-dioxygenase 1 involves complex formation and complementary charge pairing at their protein-protein interface.","authors":"Pranjal Biswas, Yue Dai, Dhanya T Jayaram, Priya Das Sinha, Saurav Misra, Jesus Tejero, Belinda Willard, Dennis J Stuehr","doi":"10.1016/j.jbc.2025.110443","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110443","url":null,"abstract":"<p><p>In eukaryotes the last steps of heme biosynthesis occur in mitochondria and so heme must be transported to reach many heme-dependent proteins that mature and function outside this organelle. Although the enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has emerged as a key intracellular heme chaperone, how it performs heme deliveries to its numerous clients is poorly understood. It is unknown if handoffs of the GAPDH-bound heme require that it make direct contact with its clients or instead involve GAPDH passing its heme to middlemen proteins to execute the final heme transfers. To address this question, we studied GAPDH heme transfer to the client protein indoleamine dioxygenase 1 (IDO1), whose activity is heme-dependent and regulates mammalian immune responses and cancer progression. A chemical crosslinking-mass spectrometry approach identified two Lys residues that formed an inter-protein crosslink across a previously uncharacterized GAPDH-IDO1 interface. This guided our building a model of the GAPDH-IDO1 complex so we could interrogate by point mutagenesis the role of the GAPDH-IDO1 contact in enabling delivery of GAPDH heme to IDO1. We characterized behaviors of the GAPDH and IDO1 variants in purified form and when expressed in the HEK293T human cell line. This revealed GAPDH heme transfer to IDO1 in cells requires that they make a direct contact which relies on a specific Lys-Asp charge pairing interaction forming across the complex interface. These findings illuminate a key step in the maturation of functional IDO1 and improve our understanding of how GAPDH may perform its heme trafficking function in mammals.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110443"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid asymmetry and membrane trafficking: transbilayer distribution of structural phospholipids as regulators of exocytosis and endocytosis.","authors":"Margherita Caputo, Olga Gubar, Petra Tóth, Nicolas Vitale, Stéphane Gasman, Stéphane Ory","doi":"10.1016/j.jbc.2025.110441","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110441","url":null,"abstract":"<p><p>The plasma membrane of eukaryotic cells is highly dynamic and asymmetrically organized. Its continuous remodeling plays a crucial role in diverse cellular processes, including apoptosis, blood coagulation, and vesicular trafficking. The distribution and rearrangement of phospholipids (PLs) within the bilayer are tightly regulated, influencing membrane curvature, tension, and organization. This review examines the role of PL asymmetry in vesicle fusion, the final step of exocytosis, and in vesicular membrane retrieval by compensatory endocytosis in neurosecretory cells, with a particular emphasis on structural PLs such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). We discuss the molecular mechanisms that maintain and disrupt PLs asymmetry and explore how lipid rearrangements affect vesicle dynamics. Additionally, we highlight recent findings on lipid scramblases, particularly phospholipid scramblase-1 (PLSCR1), and their role in regulated exocytosis and compensatory endocytosis.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110441"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting HIF-P4H-2 in APP/PS1 Alzheimer's mouse model improves glucose metabolism, reduces dystrophic neurites and maintains exploratory activity.","authors":"Margareta Kurkela, Lenka Dvořáková, Henna Koivisto, Maiju Uusitalo, Petri Kursula, Mikko Kettunen, Olli Gröhn, Heikki Tanila, Peppi Koivunen","doi":"10.1016/j.jbc.2025.110432","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110432","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common cause of dementia with limited treatment options. We asked whether activation of the hypoxia-inducible factor (HIF) pathway via genetic deficiency of HIF prolyl 4-hydoxylase-2 (HIF-P4H-2/PHD2/EGLN1) could be an AD disease modifying therapy using transgenic APP/PS1 female mice. At 12 months of age, APP/PS1/Hif-p4h-2^gt/gt mice had 20% less cortical amyloid-β (Aβ) and less dystrophic neurites around amyloid plaques compared to APP/PS1 mice used as controls. Compared to controls, APP/PS1/Hif-p4h-2^gt/gt mice were leaner, had better glucose tolerance and insulin sensitivity and higher expression levels of a HIF target, glucose transporter 1, in brain. These changes associated with lesser Aβ toxicity in APP/PS1/Hif-p4h-2^gt/gt mice linking indices of neurodegeneration with HIF-P4H-2-deficiency-mediated amelioration on brain and systemic glucose metabolism. In open field and dark-light tests, APP/PS1/Hif-p4h-2^gt/gt mice maintained their behavior during aging whereas controls showed a change by 60-80% in exploratory activity and anxiety parameters from 6 to 12 months. Maintenance of behavior associated with cortical Hif-p4h-2 mRNA downregulation, lesser Aβ toxicity and lower white adipose tissue inflammation in APP/PS1/Hif-p4h-2^gt/gt mice. Altogether, these data connect activation of the HIF pathway via HIF-P4H-2 deficiency to neuroprotection in the APP/PS1 Alzheimer's mouse model.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110432"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extensive citrullination of human serum albumin is physiological and not inherently immunogenic in rheumatoid arthritis.","authors":"Cecilia Mustelin, Archana Einstein, Xiaoxing Wang, Farheen Shaikh, Tomas Mustelin","doi":"10.1016/j.jbc.2025.110438","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110438","url":null,"abstract":"<p><p>Autoantibodies against citrullinated proteins are diagnostic of rheumatoid arthritis (RA), a chronic and systemic autoimmune condition that affects synovial joints. Proteomic studies have revealed that human serum albumin is among the proteins that are citrullinated in RA. Anti-citrullinated protein antibodies reacting with albumin have also been reported. Here, we show that albumin is citrullinated at 11 arginine residues in the blood of both RA patients and, surprisingly, in healthy donors and to a very similar stoichiometry, albeit with some subtle differences. Albumin citrullination exhibited slightly different patterns in synovial fluid from RA patients compared to RA serum-derived albumin, although overall stoichiometry was similar. Incubation of albumin with live neutrophils or recombinant protein arginine deiminases 2 or 4 at 37°C resulted in its rapid citrullination at multiple sites. Albumin citrullination reduced thyroxin binding in vitro. IgG antibodies in the serum of RA patients and healthy donors displayed comparable reactivities to physiologically citrullinated albumin. Similarly, citrullinated peptides corresponding to 14 citrullination sites, were not significantly better recognized by IgG in serum from 86 RA patients than from healthy controls, and surprisingly some were even recognized to a lesser degree in RA. The very few RA patient antibodies exceeding the 95^th percentile of the signal in healthy donors may simply represent weak cross-reactivity of antibodies against unrelated citrullinated antigens. Our findings reveal that albumin citrullination is likely physiological and of little interest to the immune system in RA patients, presumably because of persisting immunological tolerance. We discuss potential physiological functions of albumin citrullination. 250 words.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110438"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of KIR3DL1 and Human Leukocyte Antigen binding.","authors":"Martin Maiers, Yoram Louzoun, Philip Pymm, Julian P Vivian, Jamie Rossjohn, Andrew G Brooks, Philippa M Saunders","doi":"10.1016/j.jbc.2025.110437","DOIUrl":"10.1016/j.jbc.2025.110437","url":null,"abstract":"<p><p>KIR3DL1 is a polymorphic inhibitory receptor on natural killer (NK) cells that recognizes HLA class I allotypes. While the Bw4 motif spanning residues 77-83 is central to this interaction, structural studies have shown that polymorphisms elsewhere in the HLA molecule also influence binding. To address the challenge of predicting interactions across the extensive diversity of both KIR3DL1 and HLA, we developed a machine learning model trained on binding data from nine KIR3DL1 tetramers tested against a panel of HLA class I allotypes. Multiple models were evaluated using different subsets of HLA sequence features, including the full α1/α2 domains, the Bw4 motif, and α-helical residues excluding loop regions. The best-performing model, using Multi-Label-Vector Optimization (MLVO) and trained on α-helix positions, achieved AUC scores ranging from 0.74 to 0.974 across all KIR3DL1 allotypes. The model effectively distinguished high and low binders, revealing that residues beyond the Bw4 motif contribute to binding strength in a nonadditive manner. These findings demonstrate that binding affinity cannot be accurately captured by binary classifiers or single-motif rules. Our approach offers a more nuanced framework for modeling KIR3DL1-HLA interactions, with broad applicability to immunogenetic research and clinical decision-making.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110437"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-Inducible Factor 1α in Schwann cells promotes peripheral nerve myelination.","authors":"Yuka Kobayashi-Ujiie, Shuji Wakatsuki, Yurika Uematsu-Numata, Megumi Shibata, Akihito Harada, Yasuyuki Ohkawa, Nobuhito Goda, Toshiyuki Araki","doi":"10.1016/j.jbc.2025.110433","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110433","url":null,"abstract":"<p><p>Schwann cells are essential for supporting the metabolic activity of neurons and myelination in the peripheral nervous system. While hypoxia is known to influence development in aerobic organisms and has recently been shown to regulate oligodendrocyte differentiation in the central nervous system, its role in Schwann cell function remains less understood. Here we demonstrate that hypoxia-inducible factor 1α (HIF1α) in Schwann cells promotes peripheral nerve myelination. HIF1α protein expression is post-transcriptionally regulated and highly induced in myelinating Schwann cells during development and after injury. We also demonstrated that peripheral nerve tissue experiences hypoxic conditions during physiological development and during regeneration following injury. Stabilization or overexpression of HIF1α in Schwann cells promotes myelination in culture. Analysis of HIF1α targets revealed that HIF1α upregulates genes associated with Schwann cell myelination and repair. Furthermore, conditional deletion of HIF1α in Schwann cell results in delayed morphological and functional recovery from peripheral nerve injury. Together, these findings identify HIF1α as a novel regulator of Schwann cell myelination and nerve repair.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110433"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTH stimulation of Rankl transcription is regulated by SIK2 and 3 and mediated by CRTC2 and 3 through action of protein phosphatases 1, 2, 4, and 5.","authors":"Michael J Mosca, Zhiming He, Nagarajan Selvamurugan, Jobin Joseph, Whitney Petrosky, Carole Le Henaff, Nicola C Partridge","doi":"10.1016/j.jbc.2025.110434","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110434","url":null,"abstract":"<p><p>Osteoporosis is characterized by a decrease in the density and quality of bone tissue and is associated with substantial morbidity/mortality. Homeostatic processes that form new and remove old/damaged bone are dysregulated, with resultant net bone resorption. Parathyroid hormone (PTH) is a key regulator of this homeostasis and along with its analogs has been used to treat osteoporosis, however its use is limited to an \"anabolic window\". PTH stimulates both formation and resorption, the latter largely due to increased receptor activator of nuclear factor kappa-β ligand (RANKL). Our laboratory has found a cascade of messengers, Salt-inducible kinases (SIKs) and protein phosphatases (PPs) regulate nuclear translocation of CREB-regulated transcriptional coactivators (CRTCs) but the individual and/or combined contributions of these factors has not yet been established in osteoblasts. In this study, we reveal precise mechanisms involved in CRTC1/2/3 nuclear translocation and delineate their roles as co-activators of Tnfsf11 (RANKL gene name) transcription throughout osteoblast differentiation using a primary mouse calvarial osteoblast model. By performing a series of siRNA knockdowns of CRTC1/2/3, SIK1/2/3, and PP1/2/3/4/5/6/7 we determined the regulation of CRTCs upon PTH-stimulation via qPCR, quantitative immunofluorescence, Western blotting, and co-immunoprecipitation. CRTC2 is determined to be the primary co-activator of Tnfsf11 transcription with SIK2/3 inhibition upon PTH-stimulation making CRTC2 available for nuclear translocation by PP1/2/4/5 action. Understanding the mechanisms involved in this cascade may reveal novel targets in the treatment of osteoporosis and allow researchers a new line of approach for drug design that could overcome the \"anabolic window\" limiting current PTH-derived treatments.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110434"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasensitive bioluminescent reporters of Protein Kinase A based on Luciferase Activity Modulated by Phosphorylation (PKA LAMP).","authors":"Yufang Kong, Stefan Strack","doi":"10.1016/j.jbc.2025.110445","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110445","url":null,"abstract":"<p><p>We developed the novel biosensor platform Luciferase Activity Modulated by Phosphorylation (LAMP) to monitor, with unprecedented sensitivity and dynamic range, reversible protein phosphorylation in cells. Based on NanoLuc luciferase complementation (NanoBiT), LAMP sensors are small (22 kD) and provide stable and bright light output that decreases upon phosphorylation and increases upon dephosphorylation. In this report, we designed LAMP biosensors to report spatial and temporal dynamics of cAMP-dependent protein kinase A (PKA) signaling. By incorporating both PKA phosphorylation and protein phosphatase 2A (PP2A) dephosphorylation motifs into the small component of split NanoLuc (generating PKABiT/pBiT), we achieved a 7-fold dynamic range. LAMP sensors are modular and flexible, allowing the two components, LgBiT and pBiT, to be expressed as part of the same polypeptide (cis) or as part of separate, but interacting polypeptides (trans). With trans LAMP, we show that RIα and RIβ form heterodimers with activities indistinguishable from homodimers of the two PKA regulatory subunit isoforms. Cis PKA LAMP sensors revealed different activation and inactivation kinetics of endogenous, membrane anchored PKA/RI and PKA/RII holoenzymes. They also allowed us to measure kinetics of cAMP diffusion and PKA catalytic subunit translocation to the nucleus. Lastly, we used a regeneratively phosphorylated PKA LAMP sensor to identify an autoinhibitory sequence in the PP2A regulatory subunit B56δ. By tailoring the sequence of pBiT, the LAMP platform can be extended to track the activity of other protein kinases and phosphatases and second messengers they respond to, thus providing new tools for cell signaling research and drug discovery.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110445"},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Failed Cellular Surveillance Enables Pathogenic Matrix Deposition in a COL2A1-Related Osteoarthritis.","authors":"Kathryn M Yammine, Sophia Mirda Abularach, Michael Xiong, Seo-Yeon Kim, Agata A Bikovtseva, Vincent L Butty, Richard P Schiavoni, John F Bateman, Shireen R Lamandé, Matthew D Shoulders","doi":"10.1016/j.jbc.2025.110436","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110436","url":null,"abstract":"<p><p>Mutations in the COL2A1 gene, encoding procollagen-II, cause various chondrodysplasias, including precocious osteoarthritis with mild spondyloepiphyseal dysplasia engendered by the p.Arg719Cys substitution. The molecular mechanisms underlying these disorders remain incompletely understood, largely owing to the absence of models faithfully recapitulating the human disease. Here, we developed an in vitro human cartilage model using isogenic induced pluripotent stem cell (iPSC) lines carrying either wild-type or Arg719Cys COL2A1. Directed differentiation into chondrocytes yielded cartilage tissues that were analyzed by immunohistochemistry, electron microscopy, SDS-PAGE, and RNA-sequencing. Tissues derived from Arg719Cys heterozygotes displayed a deficient matrix, closely reflecting the human disease phenotype. Arg719Cys procollagen-II was excessively post-translationally modified and partially retained within the endoplasmic reticulum (ER), leading to ER distention. Notably, despite introduction of an aberrant cysteine residue-expected to engage redox-sensitive folding and quality control pathways-Arg719Cys procollagen-II was not detectably recognized by the ER proteostasis network. The resulting inability to mount a quality control response, including activation of the unfolded protein response, indicates a failure in cellular surveillance. As a result, malformed procollagen-II both accumulates intracellularly and is secreted, contributing to the deposition of a structurally compromised extracellular matrix that drives disease pathology. The iPSC-derived cartilage model presented here provides a genetically defined and expandable, human-based system for dissecting the mechanisms of failed proteostasis in collagenopathies. These findings shed light on the types of substitutions in procollagen that cells can or cannot recognize, and underscore the therapeutic potential of targeting cellular surveillance and collagen quality control pathways in COL2A1-related disorders and beyond.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110436"},"PeriodicalIF":4.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}