Biology subjects

Wei, X.

Publications and source records attributed to Wei, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

Brain injury contributes to dopaminergic neurodegeneration, Lewy body pathology, and Parkinsonism preclinically with outcomes altered by T cell modulation

Traumatic brain injury (TBI) increases the risk of Parkinsons disease (PD) development later in life, but much remains unknown regarding the mechanisms driving this relationship. A single, mild brain injury triggers resident and peripheral neuroinflammatory pathways that are similarly activated in PD patients, which could possibly increase susceptibility to neurodegeneration. In this study, we used preclinical mouse models of mild TBI (mTBI) and PD to evaluate how injury-induced immune signaling may exacerbate PD-associated pathologies. Dopaminergic (DA) neurons showed upregulation of genes associated with neuroinflammation, adaptive immunity, and PD following mTBI. mTBI caused degeneration of DA neurons in the substantia nigra (SN) and increased the spread of Lewy body (LB) pathology to other brain regions, such as the ipsilateral cortex, in a preclinical model of PD. Reducing adaptive immune infiltration into the central nervous system (CNS) with a transgenic model lacking mature lymphocytes, or directly by in vivo depletion of T cells or B cells individually, improved neurodegenerative outcomes of DA neurons following brain injury. Our results indicate the possibility of a sustained, chronic peripheral immune cell infiltration which negatively affects both DA neurons and alpha synuclein (-syn) fibril propagation, providing insight on therapeutic windows to reduce DA neuron vulnerability.

neuroscience↗

bioRxiv2025

Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair

Diabetic foot ulcers (DFUs) are a debilitating diabetes complication in which mitochondrial dysfunction and oxidative stress are prominent but mechanistically unresolved features. Here, we identify the mitochondria-encoded circular RNA circMT-RNR2 as a novel modulator of mitochondrial redox homeostasis in human skin wound healing. CircMT-RNR2 is reduced in DFU patient tissue and diabetic mouse wounds, enriched in dermal fibroblasts, and localized to mitochondria. Its loss impairs fibroblast proliferation, migration, extracellular matrix production, and contraction by destabilizing the mitochondrial antioxidant protein PRDX3, leading to elevated oxidative stress, mitochondrial damage, and mitophagy. In murine and human ex vivo wound models, circMT-RNR2 knockdown delays healing, whereas overexpression accelerates repair and boosts antioxidant defenses. These findings position circMT-RNR2 as a mitochondrial guardian of skin healing and a promising therapeutic target for DFUs. One Sentence SummaryCircMT-RNR2, a mitochondria-encoded circular RNA suppressed in diabetic foot ulcers, promotes fibroblast function and maintains mitochondrial redox balance via stabilization of the antioxidant protein PRDX3, offering a promising therapeutic target for chronic wound repair.

molecular biology↗

bioRxiv2025

Respiratory viral infections prime accelerated lung cancer growth

The COVID-19 pandemic has highlighted long-term health concerns of viral pneumonia, yet its potential impact on cancer development and growth remains poorly understood. Here, we demonstrate that prior infection with SARS-CoV-2 or influenza virus promoted lung tumor progression by reprogramming the local immune landscape. Retrospective clinical analysis revealed that patients hospitalized with COVID-19 exhibited increased lung cancer incidence. Using multiple murine lung cancer models, we show that prior severe respiratory viral infections accelerated tumor growth and reduced survival. Mechanistically, prior viral pneumonia epigenetically remodeled the lung to establish a pro-tumor microenvironment, including the local accumulation of SiglecFhi tumor-associated neutrophils, a transcriptionally reprogrammed, immunosuppressive population whose signature predicted poor prognosis in human lung adenocarcinoma. In parallel, epithelial compartments exhibited altered differentiation trajectories, with persistence of injury-associated alveolar intermediates positioned along tumorigenic lineages. We observe sustained chromatin remodeling at key cytokine loci in immune and structure cells, linking inflammatory memory to persistent immune suppression. Therapeutically, combined inhibition of neutrophil recruitment via CXCR2 and PD-L1 signaling restored CD8 T cell infiltration and suppressed tumor growth. Together, our findings establish a direct causal relationship between viral pneumonia, including COVID-19, and lung tumorigenesis, highlighting the urgent need to monitor survivors for elevated cancer risk and to develop targeted interventions and therapies aimed at preventing potential cancer bursts in COVID-19 convalescents. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/672566v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1c6705borg.highwire.dtl.DTLVardef@fa728eorg.highwire.dtl.DTLVardef@76fc6corg.highwire.dtl.DTLVardef@1b65336_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

VAMP8 function reveals tight linkage between endocytic recycling and endocytosis

Clathrin-mediated endocytosis (CME) is a multistage process that involves the initiation and stabilization of clathrin-coated pits (CCPs) that invaginate and finally detach from the plasma membrane to form clathrin-coated vesicles (CCVs). Given that SNARE proteins are essential for downstream vesicle targeting and fusion events, their recruitment into nascent CCVs has been suggested to be a prerequisite for CME progression. However, which and how SNARE proteins regulate CME remains to be explored. Here, we showed that siRNA-mediated knockdown of the R-SNARE, VAMP8 impairs CCP initiation, stabilization and invagination and strongly inhibits CME. Mechanistically, recruitment of VAMP8 to CCVs is not required for CME. Instead, depletion of VAMP8 inhibits recycling of endocytic cargoes and as exemplified here by transferrin receptor, skews their trafficking toward lysosomal degradation. VAMP8 depletion therefore indirectly impairs CCV formation and inhibits CME by depleting endocytic cargo. Overall, our study provides new insights into the crosstalk between endocytosis and endocytic recycling of CME cargo and demonstrates the critical role for cargo recruitment in stabilizing nascent CCPs to regulate CME. Significance StatementWe demonstrate that VAMP8 depletion inhibits recycling of endocytic cargo and reroutes transferrin receptors toward lysosomal degradation, thereby impairing endocytic vesicle formation and inhibiting clathrin-mediated endocytosis. Thus, the work uncovers a critical link between endocytic recycling and endocytosis, highlighting the importance of recycling pathways in maintaining membrane dynamics. However, the recruitment of VAMP8 into nascent clathrin-coated pits by CALM is not required for CME. While SNARE recruitment is essential for formation of COPI and COPII vesicles, our findings suggest that this requirement is not generalizable to endocytic CCVs.

cell biology↗

bioRxiv2025

Fast Phenotype Simulation for Genotype Representation Graphs

MotivationThe Genotype Representation Graph (GRG) [DeHaas et al., 2025] is a graph representation of whole genome polymorphisms, designed to encode the variant hard-call information in phased whole genomes. It encodes the geno-types as an extremely compact graph that can be traversed efficiently, enabling dynamic programming-style algorithms on applications such as genome-wide association studies that run faster on biobank-scale data than existing alternatives. To facilitate scalable statistical genetics, we present GrgPhenoSim, an extremely fast phenotype simulator for GRGs, suitable for simulating phenotypes on biobank-scale datasets. ResultsGrgPhenoSim contains all the primary functionalities of a phenotype simulator, uses a standardized output, and supports customized simulations. Grg-PhenoSim is dozens to hundreds of times faster than tstrait [Tagami et al., 2024], a fast ancestral recombination graph-based phenotype simulator, when the sample size ranges from thousands to hundreds of thousands samples. AvailabilityThe GrgPhenoSim library and use-case demonstrations are available at https://github.com/aprilweilab/grg_pheno_sim The documentation for GrgPhenoSim is hosted at https://grgl.readthedocs.io/en/latest/index.html

genetics↗

bioRxiv2025

ProStab: Prediction of protein stability change upon mutations by protein language and inverse folding models

Predicting protein stability change upon mutation is critical for protein engineering, yet remains limited by the modeling assumptions of physics-based methods and the generalization bottlenecks of data-driven approaches. We present ProStab, a deep learning framework that integrates sequence- and structure-based information, including the mutation-aware sequence embeddings from protein language models and the geometric features extracted via an inverse folding model. Trained on the large-scale Megascale dataset, ProStab demonstrates strong performance across diverse test sets and robust generalization across distribution shifts between the training and test sets. In head-to-head comparisons, ProStab outperforms all state-of-the-art methods with consistently higher Spearman correlation and precision. To evaluate its practical utility, we experimentally validated ProStab-predicted mutations on the model enzyme transaminase. Among the 16 successfully expressed variants, 4 exhibited improved thermal stability. Remarkably, the 1st top-ranked predicted mutation yielded the highest observed enzymatic activity, retaining three-fold that of the wild type after 10 minutes at 40 {degrees}C. To facilitate broader application, a publicly accessible web server has been developed. We envisage that ProStab provides a scalable and accurate platform for intelligent protein stability design.

bioinformatics↗

bioRxiv2025

Functional integrity of the SEL1L-HRD1 complex is critical for ERAD and organismal viability

The SEL1L-HRD1 complex represents the most evolutionarily conserved branch of endoplasmic reticulum-associated degradation (ERAD), with SEL1L acting as a key cofactor for the E3 ubiquitin ligase HRD1. While the physiological relevance of this complex has been increasingly recognized, whether SEL1L is strictly required for HRD1 function in mammals has remained unclear. Here, using complementary in vivo and in vitro approaches, we define the architecture and physiological significance of the mammalian SEL1L-HRD1 ERAD complex. Our data demonstrate that direct binding between SEL1L and HRD1 is essential for ERAD function and neonatal survival in mice. In three knock-in mouse models harboring targeted mutations at the SEL1L-HRD1 interface, we show that the L709P variant - unlike the benign P699T mutation - results in complete neonatal lethality within 30 hours of birth, a phenotype more severe than that of the partially lethal S658P variant. Mechanistically, the L709P mutation abolishes SEL1L-HRD1 interaction, disrupting substrate engagement and impairing recruitment of the E2 enzyme UBE2J1, leading to the accumulation and aggregation of misfolded proteins in the ER. Notably, these defects can be partially rescued by HRD1 overexpression, echoing findings from yeast. Together, our results provide definitive evidence that the SEL1L-HRD1 interaction is essential for ERAD activity and neonatal viability in mammals, resolving a long-standing question in ERAD biology and identifying a new therapeutic strategy for modulating ERAD activity in humans. SIGNIFICANCE STATEMENTThe endoplasmic reticulum-associated degradation (ERAD) pathway is essential for maintaining cellular proteostasis and organismal health, yet its molecular regulation in mammals remains incompletely defined. The SEL1L-HRD1 complex constitutes the central axis of this conserved pathway, but whether SEL1L is required for HRD1 function in vivo has remained unresolved. Here, using genetic mouse models and biochemical analyses, we demonstrate that the physical interaction between SEL1L and HRD1 is essential for ERAD activity and neonatal viability. These findings resolve a long-standing question in ERAD biology, provide new insights into the structural and functional organization of the mammalian ERAD machinery, and highlight the SEL1L-HRD1 interface as a potential therapeutic target for modulating ERAD activity in diseases.

cell biology↗

bioRxiv2025

Condition-dependent effects of knockdown of autophagy on C. elegans longevity

Autophagy is proposed to protect against aging by clearing damaged cellular constituents. In line with this several life-extending interventions in model organisms show some degree of autophagy dependence. In C. elegans, inhibiting autophagy can shorten, lengthen or have no effect on lifespan. Differences between published findings likely reflect variability in experimental conditions. Here we investigate the condition dependence of effects on lifespan of RNA-mediated interference (RNAi) knockdown of autophagy pathway components. Effects on interventions causing a strong Age (increased lifespan) phenotype were examined: mainly mutation of daf-2 (insulin/IGF-1 receptor), but also suppression of germline development by mutation of glp-1. Factors varied included daf-2 mutant allele class, atg gene, temperature and presence of 5-fluoro-2-deoxyuridine (FUDR). Effects on lifespan of atg RNAi proved to be highly condition dependent. Notably, for most atg genes tested lifespan was not usually reduced more in the long-lived mutant than in the wild-type control. Greater suppression was seen at 20{degrees}C for certain atg genes with daf-2(e1368) but not daf-2(e1370). At 25{degrees}C, little reduction in lifespan was seen. However, atg-18 knockdown behaved differently, suppressing daf-2 Age under all conditions, suggesting possible pleiotropic action. In wild-type C. elegans, FUDR at a high concentration caused knockdown of several atg genes to increase lifespan. Thus, depending on experimental conditions, atg knockdown can increase, decrease or have no effect on daf-2 Age. Condition dependent effects were also seen with respect to glp-1 Age. The lack of suppression of daf-2 Age by atg RNAi under most conditions questions the importance of autophagy for this phenotype. Moreover, condition dependence of effects creates a risk of possible condition selection bias.

genetics↗

bioRxiv2025

Peptide-Specific CAR T cells Recognize WT1 Promiscuously Presented by Diverse HLA Class II Alleles

Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target cancer-specific surface antigens. However, CAR T cells show limited efficacy against other blood cancers and solid tumors due to challenges in identifying suitable surface targets. Here, we present a novel approach to CAR development, targeting the intracellular Wilms tumor 1 (WT1) oncoprotein, cross-presented by surface HLA-class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1 and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This innovative approach to CAR T cell development transcends traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population. Statement of significanceThis study describes a novel CAR T therapy approach leveraging the distinctive and shared characteristic of HLA-II-peptide binding promiscuity, enabling targeting of the intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study demonstrates a viable framework for designing CAR T therapies that benefit genetically diverse patient populations.

immunology↗

bioRxiv2025

MetaNet: a scalable and integrated tool for reproducible omics network analysis

Network analysis is a powerful strategy for uncovering complex relationships in high-throughput omics datasets. However, current tools often lack scalability, flexibility, and native support for multi-omics integration, posing significant barriers for exploring complex biological networks. To address these limitations, we developed MetaNet, a high-performance R package designed to construct, visualize, and analyze biological networks from multi-omics datasets. MetaNet supports highly efficient correlation-based network construction, scalable to datasets with over 10,000 features, and includes extensive layout algorithms and visualization options compatible with both static and interactive platforms. It also provides a comprehensive suite of topological and stability metrics for in-depth network characterization. Benchmarking results show that MetaNet outperforms existing R packages by up to 100-fold in computation time and reduces memory usage by up to 50-fold. We demonstrate its utility through two case studies: (1) a longitudinal analysis of microbial co-occurrence networks showing the dynamics of the airborne microbiome, and (2) an integrative exposome-transcriptome network of more than 40,000 features, uncovering distinct regulatory impacts of biological and chemical exposures. MetaNet bridges the gap between network theory and omics application by offering a robust, reproducible, and biologically informed framework for large-scale, interpretable, and integrative network analyses across diverse omics platforms, advancing systems-level understanding in modern life sciences. MetaNet is available on the Comprehensive R Archive Network (https://cran.r-project.org/web/packages/MetaNet).

bioinformatics↗

bioRxiv2025

Deepening imaging-based spatial proteomics at high spatial resolution through controlled tissue resizing and in-situ bottom-up mass spectrometry

Understanding the spatial organization of proteins in tissues is essential for elucidating biological function, but current proteomic imaging methods face limitations in resolution, sensitivity, and multiplexing capability. Here, we present IMPACT (Imaging Mass Spectrometry for Proteome Analysis on Compressed Tissue), a hydrogel-based workflow that integrates controlled vertical tissue compression following expansion to enhance protein detection while improving spatial resolution in mass spectrometry imaging (MSI). Through a 6-fold lateral expansion and 100-fold thickness reduction, analytes were concentrated at the surface to improve detection and enable analysis of thick specimen. Coupled with optimized in-gel digestion using hybrid enzymes, IMPACT increased protein identifications 3-fold compared to conventional MSI while maintaining spatial fidelity. We demonstrate IMPACTs utility in mapping low-abundance proteins and resolving fine anatomical structures. Orthogonal validation with immunofluorescence and integration with spatial transcriptomics further reveal protein-RNA distribution discrepancies, highlighting the need for direct proteomic imaging. IMPACT bridges critical gaps in spatial proteomics by enabling high-resolution, high-sensitivity, and multiplexed untargeted protein imaging, opening new avenues for tissue biology and biomarker discovery.

biophysics↗

bioRxiv2025

Mitochondrial calcium influx-driven bioenergetics in the dopaminergic system selectively enable drug reward

Drugs of abuse hijack the brains reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here, we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca2+) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca2+ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca2+ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing in mice. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a promising therapeutic target for addiction treatment.

neuroscience↗

bioRxiv2025

Low level of viral intra-host diversity is associated with severe SFTS disease

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus that can cause severe clinical symptoms and high fatality. However, the dynamics of SFTSV intra-host diversity during infection and its association with disease severity remain unexplored. Here, we characterized SFTSV iSNVs in longitudinal clinical samples from patients with distinct clinical outcomes. Our analyses revealed that SFTSV intra-host diversity was associated with disease severity and showed distinct patterns in severe and mild cases. Severe cases exhibited paradoxically lower SFTSV intra-host diversity despite higher viral loads, likely driven by reduced selection pressure. Notably, iSNVs linked to viral replication emerged in severe cases, while iSNVs associated with immunity invasion arose in mild cases. Machine learning models showed that intra-host diversity can contribute to classification of SFTS by severity. Our findings, through the lens of within-host viral populations, highlight variations in viral-host interactions during SFTSV infection and provide potential biomarkers for predicting SFTS severity.

pathology↗

bioRxiv2025

Charting the transition from in vitro gliogenesis to the in vivo maturation of transplanted human glial progenitor cells

Neither rodent models nor in vitro studies of human cells adequately describe the molecular ontogeny of human glial progenitor cells (hGPCs). Here, we used scRNA-seq together with scATAC-Seq and CUT&TAG assessment of chromatin availability to track the in vitro genesis and in vivo differentiation of hGPCs from pluripotent stem cells (PSCs). In vitro, the hGPC pool comprised 4 transcriptionally-distinct subpopulations, each associated with a distinct pattern of chromatin accessibility and histone modification of stage-dependent genes. After the neonatal transplant of these cells into myelin-deficient shiverer mice, they differentiated further as astrocytes and oligodendrocytes. A combination of gene co-expression, motif enrichment, cell-trajectory, and cell-cell interaction analyses revealed that the host environment potentiated the context-dependent differentiation of the hGPCs, via their activation of distinct gene regulatory networks. Together, these data chart the process by which human PSC-derived GPCs are generated in vitro and diversify in vivo to mature as astrocytes and oligodendrocytes.

neuroscience↗

bioRxiv2025

Dysregulated Proline Metabolism Contributes to Subretinal Fibrosis in Neovascular AMD: Therapeutic Potential of Prolyl-4-Hydroxylase Inhibition

Subretinal fibrosis, a major cause of irreversible vision loss in neovascular age-related macular degeneration (nAMD), is driven by excessive deposition of extracellular matrix such as collagens. While proline metabolism is known to play a critical role in collagen biosynthesis and fibrosis, its involvement in subretinal fibrosis remains unclear. Here, we characterized the progression of fibrovascular lesions in JR5558 mice, observing significant molecular alterations as early as 4 weeks of age and phenotypic changes by 8 weeks. Transcriptomic and metabolomic analyses revealed elevated levels of 4-hydroxyproline, an essential component of collagen, alongside significant alterations of other fibrosis-related pathways. P4HA1, a catalytic subunit of prolyl-4-hydroxylase essential for 4-hydroxyproline biosynthesis, was prominently expressed in fibrotic lesions in retinas of JR5558 and two-stage laser-induced murine models, as well as human eyes with nAMD. Targeting P4HA1 with the small-molecule inhibitor diethyl pythiDC significantly attenuated fibrovascular lesion growth in the JR5558 murine models and reduced collagen turnover in human retinal pigment epithelium cells. Combining diethyl pythiDC with aflibercept had a stronger antifibrotic effect than monotherapies in JR5558 mice. These findings suggest a key contribution of proline metabolism, particularly proline hydroxylation, in subretinal fibrosis. Inhibiting P4HA1 with diethyl pythiDC inhibited fibrosis in the models we studied, offering a novel therapeutic strategy. Further research is warranted to explore the potential benefits of combining existing anti-angiogenic therapies with drugs that inhibit proline metabolism for the management of nAMD-associated fibrosis.

neuroscience↗

bioRxiv2025

Manipulation of the Extracellular Vesicle Biogenesis Pathway in Paternal Somatic Cells Contributes to the Phenotypic Fate of the Next Generation

Human and animal studies have shown that risk factors for certain diseases are linked to our fathers physiological and psychological condition. So far, mainly in vitro evidence indicates extracellular vesicles (EVs) as one of the potential mediators of these paternal effects. In a full in vivo model system, we demonstrate that targeting the EV biogenesis pathway within somatic cells of the male Drosophila melanogaster reproductive tract induces sex-specific phenotypic changes in the progeny. These findings highlight the critical role of the EV pathway in paternal somatic cells in shaping the phenotypic destiny of the next generation and underscore the necessity for further investigations into the mechanisms of somatic to germline information transfer.

physiology↗

bioRxiv2025

The alterations of the synthetic pathway and metabolic flux of auxin indole-3-acetic acid (IAA) govern thermotolerance in Lentinula edodes mycelia subjected to heat stress

Heat stress poses a significant constraint on the annual production of Lentinula edodes(L. edodes), a challenge that has been intensified by global warming. Previous studies have established a close relationship between intracellular indole-3-acetic acid (IAA) content and heat tolerance in L. edodes. However, the specific changes in the IAA synthesis pathway and the target genes regulated by IAA under heat stress remain unclear. We employed targeted metabolomics and transcriptomics analysis to investigate the alterations in IAA synthesis pathways and gene expression in both heat-tolerant and heat-sensitive strains at various time points during heat stress. Our findings revealed that IAA is primarily synthesized via the tryptamine (TAM) and indole-3-pyruvic acid (IPYA) pathways in L. edodes. Heat-sensitive strain Y3357 exhibited excessive accumulation of tryptamine after heat stress. Silencing of the key genes of IAA synthesis include tryptophan decarboxylase (TDC) and tryptophan transaminase (TAA) in strain S606 could reduce the thermotolerance of L. edodes mycelia. Transcriptome analysis revealed that heat-tolerant strain S606 had an earlier response to protein folding and mitochondrial gene expression compared to the heat-sensitive strain Y3357. Additionally, most genes in the MAPK signaling pathway were up-regulated after 10-24 hours of heat stress, with auxin response elements (AREs) identified in their promoters. These results suggest that the excessive tryptamine accumulation is the newly discovered limiting factor for thermotolerance, and the expression levels of key genes in the IAA synthesis pathway could directly influence hyphal thermotolerance. This study provides a new perspective on the mechanism by which IAA and the synthesis precursors affects thermotolerance of L. edodes. ImportanceAs an important plant hormone, the potential role of IAA in enhancing the heat resistance of L. edodes strains has garnered significant attention. This study systematically investigated the intracellular IAA biosynthesis pathway and its metabolic flows in L. edodes under varying durations of thermal stress, with particular emphasis on temporal gene expression patterns. Research has demonstrated that excessive accumulation of tryptamine may impair the heat stress recovery capability of L. edodes. In contrast, IAA can improve its thermotolerance by modulating the expression of genes associated with the MAPK signaling pathway.

microbiology↗

bioRxiv2025

SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells

Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet cells to generate glucagon. However, the regulatory mechanisms underlying this process remain largely unclear. Here, we report that SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD), a highly conserved protein quality control system responsible for clearing misfolded proteins from the ER, plays a key role in glucagon production by regulating turnover of the nascent proform of the PC2 enzyme (proPC2). Using a mouse model with SEL1L deletion in proglucagon-expressing cells, we observed a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we found that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein. These findings identify ERAD as a novel regulator of PC2 biology and an essential mechanism for maintaining cell function.

cell biology↗