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HRD1 IP-MS in WT and SEL1L deficiency HEK293T cells

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Liangguang Lin

LAB HEAD: Ling Qi

PROVIDER: PXD043674 | Pride | 2024-01-10

REPOSITORIES: Pride

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			Action	DRS
	HRD1_IP_MS_Abclonal_PRF-2021-L-QI-545_PRF_Q_2021_L_QI_545_50686_50691.xlsx	Xlsx
	HRD1_IP_MS_CST_PRF-2020-L-QI-410_PRF_Q_2020_L_QI_410_49748_49751_Human.xlsx	Xlsx
	PRF_Q_2020_L_QI_410_49751.msf	Msf
	PRF_Q_2020_L_QI_410_49751.raw	Raw
	PRF_Q_2021_L_QI_545_50691.msf	Msf

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Publications

SEL1L-HRD1 interaction is prerequisite for the formation of a functional HRD1 ERAD complex.

Lin Liangguang Leo LL Wei Xiaoqiong X Wang Huilun Helen HH Pederson Brent B Torres Mauricio M Lu You Y Li Zexin Jason ZJ Liu Xiaodan X Mao Hancheng H Wang Hui H Zhao Zhen Z Sun Shengyi S Qi Ling L

bioRxiv : the preprint server for biology 20230607

The SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD); however, definitive evidence for the importance of SEL1L in HRD1 ERAD is lacking. Here we report that attenuation of the interaction between SEL1L and HRD1 impairs HRD1 ERAD function and has pathological consequences in mice. Our data show that SEL1L variant p.Ser658Pro ( SEL1L S 658 P ) previously identified in Finnish Hou ...[more]

PMID: 37333389

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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 | PXD041882 | Pride

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

2023-12-17 | PXD041803 | Pride

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

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

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

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

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

2013-12-04 | GSE52929 | GEO

The mechanism to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes

Project description:Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms in the ER; however, the crosstalk between these two pathways and its physiological significance remain unexplored. Here we report that SEL1L-HRD1 ERAD limits autophagy and that, when ERAD is impaired, the ER becomes fragmented containing misfolded ER proteins or aggregates, which are subsequently cleared by autophagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL) and ER chaperones such as BiP. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process controlled by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a profound cellular adaptation capability and plasticity, centered around SEL1L-HRD1 ERAD, in dealing with misfolded proteins or protein aggregates in the ER.

2023-04-25 | PXD040899 | Pride

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

2015-05-18 | GSE56918 | GEO