About

Yair Argon, Ph.D., is an Emeritus Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. He serves as the Chief of the Division of Cell Pathology at the Children's Hospital of Philadelphia and is a member of the university's Comprehensive Cancer Center. His research focuses on the functions of molecular chaperones in the endoplasmic reticulum, particularly their roles in modulating cell surface receptors and secreted proteins. His work investigates how accessory proteins, such as molecular chaperones, regulate biosynthesis and minimize misfolding of membrane and secreted proteins. Dr. Argon's research includes studying the peptide binding and quality control functions of chaperones like BiP and GRP94, their involvement in stress responses, and their impact on cell physiology. His projects explore the molecular mechanisms of chaperone activity, their client protein interactions, and their influence on processes such as muscle recovery and amyloid fiber formation. He has developed cell-based assays to dissect chaperone functions and utilizes proteomic approaches to understand the dynamic chaperone network during physiological ER stress. His contributions advance understanding of molecular chaperones in cell biology and disease.

Research topics

• Biology
• Cell biology
• Chemistry
• Biochemistry
• Molecular biology

Selected publications

• IGF-like growth factors that couple food sensing to developmental decisions employ different release mechanisms in a single pair of <i>C. elegans</i> chemosensory neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-25

  articleOpen access

  Abstract Sensory neurons modulate organismal physiology and behavior in part by releasing neuropeptides and neurotrophins or growth factors, via the dense core vesicle (DCV) pathway. The precise matching of the sensory input to the identity of released vesicle cargo, and the timing and location of its release, is necessary to ensure appropriate responses. In some neurons, several neuropeptides or growth factors can be co-produced simultaneously, but found in distinct populations of vesicles. While this may permit their release independently of each other, in response to different stimuli, the responsible molecular pathways are not well understood. In C. elegans , the chemosensory ASI neuron pair expresses multiple neuropeptides and growth factors, including the structurally homologous C. elegans IGF-like growth factors DAF-28, INS-6, and INS-4, whose release in young larvae couples food sensing to the commitment to reproductive development. We find that these growth factors require separate molecular pathways for their release. While the axonal release of INS-6 protein required the Calcium-dependent Activator Protein for Secretion (CAPS/UNC-31), the release of DAF-28 was CAPS-independent. Consequently, the function of endogenous daf-28 , but not that of ins-6 and ins-4 , is independent of unc-31 . This difference is unexpected, as CAPS/UNC-31 is thought to control the regulated pre-synaptic/axonal release of DCV cargoes in C. elegans neurons, and demonstrates a divergence in vesicle release mechanisms. In addition, we find that mechanisms for delivering vesicles to the axons are also divergent: while neuropeptide NLP-21 was dependent on the clathrin adaptor AP-3 for its selective localization to axons, four insulin/IGF-like growth factors tested - DAF-28, INS-6, INS-4, and INS-22, were AP-3-independent for either axonal localization or function. Our data uncover molecular divergence in the pathways controlling axonal localization and release of neuropeptides and growth factors, including in a single neuron. These divergent vesicle pathways provide new means for the immediate and tunable changes in neuronal outputs, in addition to the known, less immediate mechanism of differential transcriptional regulation of DCV cargoes. Future delineation of the molecular composition of these pathways is necessary to understand how neurons match organismal responses to specific sensory inputs. Graphical Abstract Molecular divergence in the pathways controlling axonal localization and release of neuropeptides and growth factors

  PublisherOA PDFDOI

• ER oxidoreductin-1 _α and unfolded protein response as sex-dependent drivers of cardiorenal dysfunction in experimental autoimmune encephalomyelitis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-06

  preprintOpen access

  ABSTRACT Background Multiple sclerosis (MS) is associated with increased cardiovascular and renal morbidity, but mechanisms linking CNS autoimmunity to peripheral organ injury remain poorly defined. We tested the hypothesis that experimental autoimmune encephalomyelitis (EAE) induces cardiorenal dysfunction via sex-specific dysregulation of endoplasmic reticulum (ER) oxidoreductases and unfolded protein response (UPR) signaling. Methods Adult female and male C57BL/6J mice [10-12 weeks] and IRE1 α C148S knock-in mice underwent non-pertussis toxin EAE (nPTX-EAE) induced with 100µg MOG 35-55 in CFA and 200µg heat-inactivated MTB with a booster at 7 days. Controls received all components except MOG. Motor scoring was done daily and EN460 (ERO1 α inhibitor, 10 mg/kg IP) was given twice weekly beginning at 10DPI. Echocardiography and renal Doppler (Vevo 2100) were performed at 36-38DPI with primary outcomes of LV systolic/diastolic function and renal perfusion with tissue collected at 40DPI. LV and kidney were analyzed via western blot for ERO1 α , PDIA1, Prdx4, 4HNE, and BiP. Data are expressed as mean ± SEM with two-way ANOVA/Tukey’s post hoc or Mann Whitney test performed and outliers identified by ROUT (Q=1%). Results Sixty-seven percent of immunized mice developed motor deficits. At 36-38DPI, EAE reduced ejection fraction and fractional shortening while increasing IVCT, IVRT, and myocardial performance index without hypertrophy. Renal resistive index increased and end-diastolic velocity decreased in addition to reduced Bowman’s space at 40DPI. Females showed upregulated LV ERO1 α and 4HNE while males exhibited reduced PDI and Prdx4 paired with elevated BiP. EN460 attenuated cardiac and renal dysfunction and lowered LV ERO1 α /4HNE in females, but not males. IRE1 α C148S mitigated cardiac dysfunction in males and restore renal indices in both sexes. Conclusions nPTX-EAE causes clinically relevant, sex-specific cardiorenal dysfunction linked to distinct ER stress/UPR alterations. ERO1 α inhibition protects females, whereas enhanced IRE1 α activity protects males and kidneys across sexes, supporting sex-specific ER stress–targeted therapies for MS-associated cardiorenal disease.

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• Deficient glycan extension and endoplasmic reticulum stresses in <scp>ALG3‐CDG</scp>

  Journal of Inherited Metabolic Disease · 2024-04-10 · 5 citations

  articleOpen access

  Abstract ALG3‐CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol‐P‐Man to Dol‐PP‐Man 5 GlcNAc 2 (Man5) forming Dol‐PP‐Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3‐CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER‐associated degradation activities are increased in ALG3‐CDG patient‐derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1‐α pathway. In addition, we show that N‐linked Man3‐4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non‐hepatic origin. We found that like other CDGs such as ALG1‐ or PMM2‐CDG, in transferrin, the assembling intermediate Man5 in ALG3‐CDG, are likely further processed into a distinct glycan, NeuAc 1 Gal 1 GlcNAc 1 Man 3 GlcNAc 2 , probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono‐antennary glycan with the same molecular weight as the truncated glycan described in MGAT2‐CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3‐CDG which will have important implications in the pathogenesis of CDG.

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• Increased activity of <scp>IRE1</scp> improves the clinical presentation of <scp>EAE</scp>

  The FASEB Journal · 2023-11-20 · 4 citations

  articleOpen accessSenior authorCorresponding

  Activation of the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme-1α (IRE1α) contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the contrary, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells but exhibited a beneficial effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Although mechanical allodynia was unaffected, significant improvement in motor function was found in IRE1C148S mice with EAE relative to wild type (WT) mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of proinflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) levels, suggesting improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the microglial activation marker ionized calcium-binding adapter molecule (IBA1), along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be beneficial in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.

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• The RIDD activity of <i>C. elegans</i> IRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-12

  preprintOpen access

  Abstract Xbp1 splicing and regulated IRE1-dependent RNA decay (RIDD) are two RNase activities of the ER stress sensor IRE1. While Xbp1 splicing has important roles in stress responses and animal physiology, the physiological role(s) of RIDD remain enigmatic. Genetic evidence in C. elegans connects XBP1-independent IRE1 activity to organismal stress adaptation, but whether this is via RIDD, and what are the targets is yet unknown. We show that cytosolic kinase/RNase domain of C. elegans IRE1 is indeed capable of RIDD in human cells, and that sensory neurons use RIDD to signal environmental stress, by degrading mRNA of TGFβ-like growth factor DAF-7. daf-7 was degraded in human cells by both human and worm IRE1 RNAse activity with same efficiency and specificity as Blos1, confirming daf-7 as RIDD substrate. Surprisingly, daf-7 degradation in vivo was triggered by concentrations of ER stressor tunicamycin too low for xbp-1 splicing. Decrease in DAF-7 normally signals food limitation and harsh environment, triggering adaptive changes to promote population survival. Because C. elegans is a bacteriovore, and tunicamycin, like other common ER stressors, is an antibiotic secreted by Streptomyces spp. , we asked whether daf-7 degradation by RIDD could signal pending food deprivation. Indeed, pre-emptive tunicamycin exposure increased survival of C. elegans populations under food limiting/high temperature stress, and this protection was abrogated by overexpression of DAF-7. Thus, C. elegans uses stress-inducing metabolites in its environment as danger signals, and employs IRE1’s RIDD activity to modulate the neuroendocrine signaling for survival of upcoming environmental challenge.

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• Increased activity of IRE1 improves the clinical presentation of EAE

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-04-20

  preprintOpen accessSenior authorCorresponding

  Abstract Activation of the ER stress sensor IRE1α contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo . On the other hand, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells, but exhibited a strong protective effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Significant improvement in motor function was found in IRE1C148S mice with EAE relative to WT mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of pro-inflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced CNPase levels, suggestiing improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the activation of microglial activation marker IBA1, along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be protective in vivo , and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of the ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.

  PublisherOA PDFDOI

• Correction for Bagashev et al., “CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum”

  Molecular and Cellular Biology · 2022-08-17

  erratumOpen access

  This article refers to:CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum

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• Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model

  Blood Advances · 2022-12-12 · 20 citations

  articleOpen access

  Extracellular protein disulfide isomerases (PDIs), including PDI, endoplasmic reticulum protein 57 (ERp57), ERp72, ERp46, and ERp5, are required for in vivo thrombus formation in mice. Platelets secrete PDIs upon activation, which regulate platelet aggregation. However, platelets secrete only ∼10% of their PDI content extracellularly. The intracellular role of PDIs in platelet function is unknown. Here, we aim to characterize the role of ERp5 (gene Pdia6) using platelet conditional knockout mice, platelet factor 4 (Pf4) Cre+/ERp5floxed (fl)/fl. Pf4Cre+/ERp5fl/fl mice developed mild macrothrombocytopenia. Platelets deficient in ERp5 showed marked dysregulation of their ER, indicated by a twofold upregulation of ER proteins, including PDI, ERp57, ERp72, ERp46, 78 kilodalton glucose-regulated protein (GRP78), and calreticulin. ERp5-deficient platelets showed an enhanced ER stress response to ex vivo and in vivo ER stress inducers, with enhanced phosphorylation of eukaryotic translation initiation factor 2A and inositol-requiring enzyme 1 (IRE1). ERp5 deficiency was associated with increased secretion of PDIs, an enhanced response to thromboxane A2 receptor activation, and increased thrombus formation in vivo. Our results support that ERp5 acts as a negative regulator of ER stress responses in platelets and highlight the importance of a disulfide isomerase in platelet ER homeostasis. The results also indicate a previously unanticipated role of platelet ER stress in platelet secretion and thrombosis. This may have important implications for the therapeutic applications of ER stress inhibitors in thrombosis.

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• Loss of AID exacerbates the malignant progression of CLL

  Leukemia · 2022-08-30 · 1 citations

  articleOpen access

  Abstract Activation-induced cytidine deaminase (AID) has been implicated as both a positive and a negative factor in the progression of B cell chronic lymphocytic leukemia (CLL), but the role that it plays in the development and progression of this disease is still unclear. We generated an AID knockout CLL mouse model, AID −/− /Eμ-TCL1, and found that these mice die significantly earlier than their AID-proficient counterparts. AID-deficient CLL cells exhibit a higher ER stress response compared to Eμ-TCL1 controls, particularly through activation of the IRE1/XBP1s pathway. The increased production of secretory IgM in AID-deficient CLL cells contributes to their elevated expression levels of XBP1s, while secretory IgM-deficient CLL cells express less XBP1s. This increase in XBP1s in turn leads AID-deficient CLL cells to exhibit higher levels of B cell receptor signaling, supporting leukemic growth and survival. Further, AID −/− /Eμ-TCL1 CLL cells downregulate the tumor suppressive SMAD1/S1PR2 pathway and have altered homing to non-lymphoid organs. Notably, CLL cells from patients with IgHV-unmutated disease express higher levels of XBP1s mRNA compared to those from patients with IgHV-mutated CLL. Our studies thus reveal novel mechanisms by which the loss of AID leads to worsened CLL and may explain why unmutated CLL is more aggressive than mutated CLL.

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• An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation

  Journal of Biological Chemistry · 2021-01-01 · 6 citations

  articleOpen accessSenior authorCorresponding

  The unfolded protein response plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum stress via biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that, upon sensing unfolded proteins via its endoplasmic reticulum luminal domain, IRE1α dimerizes and then oligomerizes (often visualized as clustering). Once assembled, the kinase domain trans-autophosphorylates a neighboring IRE1α, inducing a conformational change that activates the RNase effector domain. However, the full details of how the signal is transmitted are not known. Here, we describe a previously unrecognized role for helix αK, located between the kinase and RNase domains of IRE1α, in conveying this critical conformational change. Using constructs containing mutations within this interdomain helix, we show that distinct substitutions affect oligomerization, kinase activity, and the RNase activity of IRE1α differentially. Furthermore, using both biochemical and computational methods, we found that different residues at position 827 specify distinct conformations at distal sites of the protein, such as in the RNase domain. Of importance, an RNase-inactive mutant, L827P, can still dimerize with wildtype monomers, but this mutation inactivates the wildtype molecule and renders leukemic cells more susceptible to stress. We surmise that helix αK is a conduit for the activation of IRE1α in response to stress.

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Recent grants

• NIH Grant R21NS059367

  NIH · $206k · 2010

• NIH Grant R21AI088376

  NIH · $458k · 2013

• NIH Grant R01AG018001

  NIH · $5.9M · 2019

• NIH Grant P01AI023282

  NIH · $1.1M · 1990

• NIH Grant R01AI030178

  NIH · $3.4M · 2005

Frequent coauthors

• Janis K. Burkhardt

  Children's Hospital of Philadelphia

  60 shared

• Davide Eletto

  ETH Zurich

  40 shared

• Tali Gidalevitz

  Drexel University

  39 shared

• Daniela Ricci

  Université Paris Cité

  38 shared

• Susan Hester

  Research Triangle Park Foundation

  38 shared

• Daniela Eletto

  University of Salerno

  36 shared

• Chhanda Biswas

  Jawaharlal Nehru Medical College Hospital

  34 shared

• Jeanne L. Dul

  34 shared

Labs

• Pathology and Laboratory MedicinePI

Education

• PhD, Biological Chemistry

  Harvard University

  1979

Awards & honors

• Fellow, Medical Research Council Lab of Molecular Biology, C…
• Fellow, Hebrew University Medical School, Jerusalem, Israel…