Biology subjects

Argon, Y.

Publications and source records attributed to Argon, Y..

5 recordsLinked to original sources

bioRxiv2026

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

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 AbstractMolecular divergence in the pathways controlling axonal localization and release of neuropeptides and growth factors O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/701173v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@9cba54org.highwire.dtl.DTLVardef@18d1881org.highwire.dtl.DTLVardef@43d069org.highwire.dtl.DTLVardef@27c7b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

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

BackgroundMultiple 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. MethodsAdult female and male C57BL/6J mice [10-12 weeks] and IRE1C148S knock-in mice underwent non-pertussis toxin EAE (nPTX-EAE) induced with 100{micro}g MOG35-55 in CFA and 200{micro}g heat-inactivated MTB with a booster at 7 days. Controls received all components except MOG. Motor scoring was done daily and EN460 (ERO1 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, PDIA1, Prdx4, 4HNE, and BiP. Data are expressed as mean {+/-} SEM with two-way ANOVA/Tukeys post hoc or Mann Whitney test performed and outliers identified by ROUT (Q=1%). ResultsSixty-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 Bowmans space at 40DPI. Females showed upregulated LV ERO1 and 4HNE while males exhibited reduced PDI and Prdx4 paired with elevated BiP. EN460 attenuated cardiac and renal dysfunction and lowered LV ERO1/4HNE in females, but not males. IRE1C148S mitigated cardiac dysfunction in males and restore renal indices in both sexes. ConclusionsnPTX-EAE causes clinically relevant, sex-specific cardiorenal dysfunction linked to distinct ER stress/UPR alterations. ERO1 inhibition protects females, whereas enhanced IRE1 activity protects males and kidneys across sexes, supporting sex-specific ER stress-targeted therapies for MS-associated cardiorenal disease.

molecular biology↗

bioRxiv2023

The RIDD activity of C. elegans IRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival

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 TGF{beta}-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 IRE1s RIDD activity to modulate the neuroendocrine signaling for survival of upcoming environmental challenge.

cell biology↗

bioRxiv2023

Increased activity of IRE1 improves the clinical presentation of EAE

Activation of the ER stress sensor IRE1 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 IRE1, we used a mouse model expressing a C148S variant of IRE1 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 IRE1 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.

neuroscience↗

bioRxiv2020

The connector between the kinase and RNase domains of IRE1α transmits the conformational change that underlies ER stress-induced activation.

The unfolded protein response (UPR) plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1 is a major transducer that conveys endoplasmic reticulum (ER) stress to 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 ER luminal domain, IRE1 dimerizes and oligomerizes (often visualized as clustering), and then trans-autophosphorylates. The IRE1 kinase activity is required for activation of its RNase effector domain and for clustering of IRE1. It is not yet clear if IRE1 clustering is a platform for the RNase activity, or if the two represent distinct biological functions. Here, we uncover a previously unrecognized role for helix K between IRE1 kinase and RNase domains in conveying critical conformational changes. Using mutants within this inter-domain helix, we show for the first time that: 1) distinct substitutions (specifically, of Leu827) selectively affect oligomerization, RNase activity, and, unexpectedly, the kinase activity of IRE1; 2) RNase activation can be uncoupled from IRE1 oligomerization, and phosphorylation of S729 marks the former but not the latter; 3) The nature of residue 827 determines the conformation that the IRE1 protein adopts, leading to different patterns of biochemical activities. In summary, this work reveals a previously unappreciated role for the inter-domain helix as a pivotal conduit for attaining the stress-responsive conformation of IRE1.

biochemistry↗