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Sel1L-Hrd1 ERAD is required for the maintainenance of beta cell identity and function

ABSTRACT: Mice with Sel1L deficient beta cells develop severe hyperglycemia, glucose intolerance and impaired insulin secretion. Using single cell sequencing, we identified that Sel1L plays a major role in maintaining beta cell maturation by suppressing TGF-beta signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE137785 | GEO | 2022/09/17

REPOSITORIES: GEO

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Transcriptomic responses to SEL1L-HRD1 ERAD deficiency in HEK293T cells and mouse brown adipose tissue

Project description:The mamallian SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) complex is essential for retrotranslocation and degradatin of misfolded proteins in the ER. HRD1 is an E3-ligase with multiple transmembrane domains that consititute the retrotranslocation channel, while its cofactor SEL1L is responsible for the stability of the complex and for substrate recruitment. This study aims to identify transcriptionally-regulated genes responding to SEL1L-HRD1 ERAD deficiency in two different mammalian cell types.

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Regulation of endoplasmic reticulum-mitochondria contacts and mitochondrial dynamics by Sel1L-Hrd1 ERAD during thermogenesis

Project description:Organelles such as endoplasmic reticulum (ER) and mitochondria interact with each other at specialized domains on the ER known as mitochondria-associated membranes (MAMs). Here, using three-dimensional high-resolution imaging techniques, we show that the Sel1LHrd1 protein complex, the most conserved branch of ER-associated protein degradation (ERAD), exerts a profound impact on ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover and hence the abundance of the MAM protein sigma receptor 1 (SigmaR1). Sel1L or Hrd1 deficiency in brown adipocytes impairs dynamic interaction between ER and mitochondria, leading to the formation of pleomorphic “megamitochondria” and, in some cases with penetrating ER tubule(s), in response to acute cold challenge. Mice with ERAD deficiency are cold sensitive and exhibit mitochondrial dysfunction in brown adipocytes. Mechanistically, endogenous SigmaR1 is targeted for proteasomal degradation by Sel1L-Hrd1 ERAD, whose accumulation in ERAD-deficient cells leads to mitofusin 2 (Mfn2) oligomerization, thereby linking ERAD to mitochondrial dynamics. Our study identifies Sel1L-Hrd1 ERAD as a critical determinant of ER-mitochondria contacts, thereby regulating mitochondrial dynamics and thermogenesis.

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Hepatic Sel1L-Hrd1 ER-Associated Degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

Project description:Fibroblast growth factor 21 (Fgf21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting-feeding. The Sel1LHrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)- associated degradation (ERAD) machinery. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1LHrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh, while having no effect on the other well-known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L-Hrd1 ERAD and Crebh-Fgf21 levels under fasting-feeding and growth. This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERADCrebh- Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.

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Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 involved in endoplasmic reticulum-associated degradation (ERAD). Its physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we provide the first in vivo evidence that Sel1L is indispensable for Hrd1 stability, ER homeostasis and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 weeks with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation and promotes cell death. Serendipitously, using biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of mammalian ERAD and ER homeostasis, which is essential for protein translation, pancreatic function, cellular and organismal survival. Pancreas tissue of wild type and inducible Sel1L knockout mice were subjected to gene expression analysis.

2013-12-04 | E-GEOD-52929 | biostudies-arrayexpress

Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

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HRD1 IP-MS in WT and SEL1L deficiency HEK293T cells

Project description:To gain further insights into the role and importance of SEL1L in HRD1 ERAD, we performed unbiased proteomics LC-MS analyses to map SEL1L and HRD1 interactomes in WT and SEL1L-/-, WT and HRD1-/- HEK293T cells, respectively.

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ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling

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.

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