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ER-associated degradation maintains postnatal muscle hypertophy and systemic energy metabolism

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE237194 | GEO | 2023/07/17

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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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

2013-12-04 | GSE52929 | GEO

The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

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

IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation

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

The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

2015-05-18 | GSE56918 | GEO

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.

2020-04-24 | GSE145895 | GEO

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.

2018-08-17 | GSE118658 | GEO

IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation

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

Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its vital importance in the biogenesis of glycosylphosphatidylinositol-anchored proteins

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

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