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Neuronal SEL1L-HRD1 ERAD regulates one-carbon metabolism and is essential for motor function and survival

ABSTRACT: SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) is essential for protein folding quality control and maintaining homeostasis in the ER. Defects in SEL1L-HRD1 ERAD complex has been linked to early onset of severe neurological syndromes. However, its physiological importance and underlying mechanisms in neurons remain poorly understood. This study established a mouse model with neuron-specific deletion of Sel1L and revealed that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability.

ORGANISM(S): Mus musculus

PROVIDER: GSE299894 | GEO | 2026/02/10

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.

2023-12-17 | GSE231583 | GEO

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

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

Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

2013-12-04 | GSE52929 | GEO

Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD

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

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

SEL1L is Dispensable for ER Homeostasis and Function in Spermatogenic Cells

Project description:The SEL1L-HRD1 complex is a critical component of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway, essential for maintaining ER homeostasis and cellular function. While the importance of SEL1L and HRD1 in various physiological processes have been reported in mice and humans, their specific functions in male germ cells remain unexplored. This study aims to investigate the role of SEL1L-HRD1 ERAD in spermatogenesis process. To achieve this, we conducted whole genome RNA sequencing to identify genes differentially regulated in testes from male germ cell specific SEL1L-deficient mice.

2025-05-06 | GSE292552 | GEO

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.

2024-01-10 | PXD043674 | Pride

Hepatic Sel1L-Hrd1 ER-associated degradation deficiency leads to intrahepatic cholestasis in mice

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

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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