ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling
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ABSTRACT:
PROVIDER: PRJNA601502 | ENA |
REPOSITORIES: ENA
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Project description:β cell apoptosis and dedifferentiation are two hotly-debated mechanisms underlying β cell loss in type 2 diabetes (T2D); however, the molecular drivers underlying such events remain largely unclear. Here, by performing a side-by-side comparison of mice carrying β cell-specific deletion of endoplasmic reticulum (ER)-associated degradation (ERAD) and autophagy, we report that while autophagy appears necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex is required for the maintenance of β cell maturation and identity. Notably, SEL1L expression is significantly reduced in human T2D islets compared to healthy human islets. At the single cell level, we demonstrate that Sel1L deficiency is not associated with β cell loss, but rather loss of β cell identity. Mechanistically, we find that Sel1L-Hrd1 ERAD controls β cell identity via TGFβ signaling, in part by mediating the degradation of TGF-β receptor 1 (TGFβRI). Inhibition of TGFβ signaling in Sel1L-deficient β cells augments the expression of β cell maturation markers and increases the total insulin content. Our data reveal profound but distinct pathogenic effects of two major proteolytic pathways in β cells, providing a new framework for therapies targeting distinct mechanisms of protein quality control.
2020-06-29 | GSE143757 | GEO
Project description:The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass.
2024-04-13 | GSE263565 | GEO
Project description:ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs
2024-08-20 | PXD055020 |
Project description:Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration
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Project description:Cortical interneuron diversity arises from the interplay of intrinsic developmental patterning and local extrinsic cues. While individual genetic programs underlying cardinal cell type identity are established in immature neurons prior to integration into cortical circuits, it remains unclear whether distinct interneuron subtype identities are pre-established, and if so, how their identity is maintained prior to circuit integration. Sox6 is a transcription factor with an established role in the maturation of interneurons derived from the medial ganglionic eminence and cell-type specification in other neuronal and non-neuronal cells. To determine a possible role in maintaining cortical somatostatin-expressing (Sst+) interneuron subtype identity, we conditionally removed Sox6 (Sox6-cKO) in migrating Sst+ interneurons and assessed the effects on their mature identity. In adolescent animals, five of eight molecular Sst+ subtypes were nearly absent in the cortex of Sox6-cKO mice. This reduced subtype diversity was not due to a decrease in the overall number of Sst+ interneurons and cells displayed electrophysiological maturity and expressed genes enriched within the broad class of Sst+ interneurons. Furthermore, we show that at embryonic day 18.5, prior to cortical integration, mature Sst+ cell subtype identity could already be inferred in both control and Sox6-cKO cortices, suggesting that the loss in subtype diversity observed in the mature cortex is due to a disrupted subtype maintenance. Importantly, Sox6 removal at postnatal day 7, after Sst+ interneurons have finished migrating and begun integration into the network, did not disrupt marker expression of Sst+ subtypes in the mature cortex. Therefore, Sox6 is necessary during this migratory phase for maintenance of Sst+ subtypes identity, indicating that subtype maintenance requires active transcriptional programs during migration.
2023-08-25 | GSE233791 | GEO
Project description:The maintenance and persistence of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways that contribute to the loss of CD8+ T cells are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence and identifying patients whose T cells could function best for treatment. Here, we demonstrate the experience of endoplasmic reticulum (ER) stress in differentiating murine CD8+ T cells in vitro and in vivo. ER-associated degradation (ERAD) adapter Sel1L was found to be selectively induced in activated CD8+ T cells. Loss of Sel1L limited CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal T cell oxidative metabolism and mitochondrial fusion. Finally, we demonstrate that human CD8+ T cells experience ER stress after activation and that ER stress is negatively associated with improved T cell functionality in bispecific antibody therapy and chimeric antigen receptor T cell therapy. Together these results demonstrated that ER stress and ERAD are important and novel regulators of T cell function and persistence.
2024-04-25 | GSE244315 | GEO
Project description:The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum is largely unknown. Here, we report that the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and significant reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beiging of adipocytes, and resistance to diet induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.
2023-07-17 | GSE237194 | GEO
Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), but its physiological role in a cell-type-specific manner remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Mechanistically, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Further biochemical analyses revealed that Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and prone to the formation of protein aggregates, which are degraded by autophagy-mediated degradation. The Sel1L-mediated control of LPL secretion is seen in other LPL-expressing cell types as well such as cardiac muscle and macrophages. Thus, our study reports a novel role of Sel1L in LPL secretion and systemic lipid metabolism. Sel1Lflox/flox mice were crossed with adiponectin promoter driven Cre mice to create adipose tissue-specific Sel1L-/- mice. Male wildtype C57Bl/6 mice and adipose tissue-specific Sel1l-/- mice were fed a high fat diet (Research Diets D12492) for 5 weeks. Adipose tissue was excised and used for microarray analysis.
2015-05-18 | E-GEOD-56918 | biostudies-arrayexpress
Project description:ER-associated degradation maintains postnatal muscle hypertophy and systemic energy metabolism
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Project description:The neural crest is a highly plastic stem cell population that represents a notable exception to the germ layer theory. Despite being of ectodermal origin, these cells can differentiate into skeletal derivatives like cartilage and bone, tissues that are typically formed by mesoderm. The inductive program that endows the neural crest with these unique properties is still poorly understood. Here, we report that Smad2/3-mediated TGFβ signaling endows cranial neural crest cells with enhanced developmental potential. Our results show that TGFβ signaling modulates neural crest axial identity and directly activates the gene circuits that support skeletal differentiation. Cooperation between TGFβ and low levels of WNT-signaling in the embryonic head activates cranial-specific cis-regulatory elements of anterior genes. Activation of the TGFβ pathway allowed reprogramming of trunk neural crest cells to adopt an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGFβ signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.
2025-01-19 | GSE175808 | GEO