Regulation of endoplasmic reticulum-mitochondria contacts and mitochondrial dynamics by Sel1L-Hrd1 ERAD during thermogenesis
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PROVIDER: PRJNA608688 | ENA |
REPOSITORIES: ENA
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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.
2020-04-24 | GSE145895 | GEO
Project description:Endoplasmic reticulum-associated degradation (ERAD) represents a principle quality control (QC) mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unknown. Here we discover that IRE1alpha, the sensor of unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. Mechanistically, ERAD-mediated IRE1alpha degradation occurs in a Bip-dependent manner under basal conditions and is attenuated in response to ER stress. Both intramembrane hydrophilic residues of IRE1alpha and lectin protein OS9 are required for IRE1alpha degradation. ERAD deficiency causes IRE1alpha protein stabilization, accumulation and mild activation both in vitro and in vivo, leading to cellular hypersensitivity to ER stress and inflammation. Furthermore, though enterocyte-specific Sel1L-knockout mice (Sel1LÎ?IEC) are viable and appear normal, they are more susceptible to experimental colitis in an IRE1alpha-dependent but CHOP-independent manner. Collectively, these results demonstrate that Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1alpha signaling in vivo by managing its protein turnover. Colon epithelium of wild type and enterocyte-specific Sel1L knockout mice were subjected to gene expression analysis.
2015-11-04 | E-GEOD-70563 | biostudies-arrayexpress
Project description:Endoplasmic reticulum-associated degradation (ERAD) represents a principle quality control (QC) mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unknown. Here we discover that IRE1alpha, the sensor of unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. Mechanistically, ERAD-mediated IRE1alpha degradation occurs in a Bip-dependent manner under basal conditions and is attenuated in response to ER stress. Both intramembrane hydrophilic residues of IRE1alpha and lectin protein OS9 are required for IRE1alpha degradation. ERAD deficiency causes IRE1alpha protein stabilization, accumulation and mild activation both in vitro and in vivo, leading to cellular hypersensitivity to ER stress and inflammation. Furthermore, though enterocyte-specific Sel1L-knockout mice (Sel1LΔIEC) are viable and appear normal, they are more susceptible to experimental colitis in an IRE1alpha-dependent but CHOP-independent manner. Collectively, these results demonstrate that Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1alpha signaling in vivo by managing its protein turnover.
2015-11-04 | GSE70563 | GEO
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.
2023-12-17 | GSE231583 | GEO
Project description:β -selection imposes a considerable demand for new protein synthesis of the newly rearranged Tcrβ gene and the multiple factors that execute the transcriptional and metabolic programs demanded by DN thymocyte proliferation. However, how proteome homeostasis or “proteostasis” is regulated during thymocyte development is largely unknown. Here, we show that the endoplasmic reticulum (ER)- associated degradation (ERAD), but not the unfolded protein response (UPR), is the master regulator of physiological ER proteostasis in immature DN thymocytes. The ERAD machinery was critically required for successful β-selection of DN3 thymocytes and consequently, ERAD deficiency impeded αβ T cell development. The Sel1L-Hrd1 complex is the most conserved branch of mammalian ERAD machinery. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. This study revealed the stringent protein quality control through the SEL1L-ERAD pathway is required for successful b-selection and the development of the ab T cells that mediate adaptive immunity.
2021-05-07 | GSE173993 | GEO
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.
2024-01-10 | PXD043674 | Pride
Project description:Impaired secretion of an essential blood coagulation factor fibrinogen leads to hepatic fibrinogen storage disease (HFSD), characterized by the presence of fibrinogen-positive inclusion bodies and hypofibrinogenemia. However, the molecular mechanisms underlying the biogenesis of fibrinogen in the endoplasmic reticulum (ER) remains unexplored. Here we uncovered a key role of SEL1L-HRD1 complex of ER-associated degradation (ERAD) in the formation of aberrant inclusion bodies, and the biogenesis of nascent fibrinogen protein complex in hepatocytes. Serendipitously, acute or chronic deficiency of SEL1L-HRD1 ERAD, but not UPR sensor IRE1α, in the hepatocytes led to the formation of hepatocellular inclusion bodies. Proteomics studies followed by biochemical assays revealed fibrinogen, not albumin or α1-antitrypsin, as a major component of the inclusion bodies. Degradation of misfolded endogenous fibrinogen Aα, Bβ, and γ chains by SEL1L-HRD1 ERAD was required for the formation of a functional fibrinogen complex in the ER. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD indeed degraded and thereby attenuated the pathogenicity of a disease-causing fibrinogen γ mutant. Together, this study demonstrates an essential role of SEL1L-HRD1 ERAD in fibrinogen biogenesis and provides novel insights into the pathogenesis of protein-misfolding diseases.
2024-09-11 | PXD047658 | Pride
Project description:The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.
2023-03-11 | PXD035243 | Pride
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.
2018-08-17 | GSE118658 | GEO
Project description:The SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) plays indispensable roles for many physiological processes in a substrate-specific manner; however, the nature of endogenous substrates remains largely elusive. Here we have developed a unique proteomics strategy based on the intrinsic property of the SEL1L-HRD1 ERAD complex to identify potential endogenous ERAD substrates in human kidney cell line HEK293T and mouse brown adipocytes. Over 100 potential substrates involved in many cellular processes, including both membrane and luminal proteins regardless of their glycosylation and disulfide bond status, are identified in each cell type, among which 34 are shared. We further uncover SEL1L-HRD1 ERAD as a suppressor of the biogenesis of glycosylphosphatidylinositol (GPI)-anchored proteins via degrading a key subunit of the GPI-transamidase complex known as phosphatidylinositol glycan anchor biosynthesis class K protein (PIGK). Lastly, several PIGK disease variants are highly unstable and quickly degraded by SEL1L-HRD1 ERAD. This study shows the most effective way to identify cell type-specific proteome-wide potential endogenous SEL1L-HRD1 substrates, and uncovers a new function of SEL1L-HRD1 ERAD in the biogenesis and disease pathogenesis associated with GPI-anchored proteins
2023-12-17 | PXD041803 | Pride