Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Sun, Shengyi; Shi, Guojun; Han, Xuemei; Francisco, Adam B.; Ji, Yewei; Mendonça, Nuno; Liu, Xiaojing; Locasale, Jason W.; Simpson, Kenneth W.; Duhamel, G; Kersten, Sander; Yates, John R.; Long, Qiaoming; Qi, Ling

doi:10.1073/pnas.1318114111

Cited by 163 publications

(278 citation statements)

References 65 publications

(96 reference statements)

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“…In transgenic mouse models of P56S, there was evidence of increased ER stress, as we saw in patient cells 8, 17. The mRNA expression profile in our patient showed a pattern indicative of ER stress, with an increase in chaperones, PERK pathway genes, and spliced XBP1, as has been reported in other disease models 18, 19. Induction of ER stress and the UPR could protect the cells from protein misfolding and dysfunction caused by the P56S mutation.…”

Section: Discussionsupporting

confidence: 83%

Nucleocytoplasmic transport defect in a North American patient with ALS8

Guber

Schindler

Budron

et al. 2018

Ann Clin Transl Neurol

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Amyotrophic lateral sclerosis 8 (ALS8) is a rare progressive neurodegenerative disease resulting from mutation in the gene for vesicle‐associated membrane protein‐associated protein B. We evaluated a North American patient using exome sequencing, and identified a P56S mutation. The disease protein had similar subcellular localization and expression levels in the patient and control fibroblasts. Patient fibroblasts showed increased basal endoplasmic reticulum stress and dysfunction of nucleocytoplasmic transport as evidenced by impaired Ran trafficking. This finding extends the identification of ALS8 into North America, and indicates a cellular defect similar to other forms of hereditary motor neuron disease.

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Section: Discussionsupporting

confidence: 83%

Nucleocytoplasmic transport defect in a North American patient with ALS8

Guber

Schindler

Budron

et al. 2018

Ann Clin Transl Neurol

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“…Certainly these approaches are useful in studying aspects of the HRD pathway although caution must be exerted in marginalization of Hrd3 in the light of its unveiled importance in Hrd1 action. Because the Hrd3 homolog SEL1-L similarly stabilizes Hrd1 in mammalian cells (26), these studies of the dual roles of Hrd3 as a stabilizer and an activator will have interesting connections to the larger eukaryotes; we anticipate SEL1-L will be similarly involved in both ensuring Hrd1 levels and activity in the mammalian context as well.…”

Section: Discussionmentioning

confidence: 94%

Direct and essential function for Hrd3 in ER-associated degradation

Vashistha

Neal

Singh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The HRD (HMG-CoA reductase degradation) pathway is a conserved route of endoplasmic reticulum-associated degradation (ERAD), by which misfolded ER proteins are ubiquitinated and degraded. ERAD substrates are ubiquitinated by the action of the Hrd1 RING-H2 E3 ligase. Hrd1 is always present in a stoichiometric complex with the ER membrane protein Hrd3, which is also required for HRD-dependent degradation. Despite its conserved presence, unequivocal study of Hrd3 function has been precluded by its central role in Hrd1 stability. Loss of Hrd3 causes unrestricted self-degradation of Hrd1, resulting in significant loss of the core ligase. Accordingly, the degree to which Hrd3 functions independently of Hrd1 stabilization has remained unresolved. By capitalizing on our studies of Usa1 in Hrd1 degradation, we have devised a new approach to evaluate Hrd3 functions in ERAD. We now show that Hrd3 has a direct and critical role in ERAD in addition to Hrd1 stabilization. This direct component of Hrd3 is phenotypically as important as Hrd1 in the native HRD complex. Hrd3 was required the E3 activity of Hrd1, rather than substrate or E2 recruitment to Hrd1. Although Hrd1 can function in some circumstances independent of Hrd3, these studies show an indispensable role for Hrd3 in living cells.highly conserved quality control pathway responsible for the degradation of both misfolded and normal proteins that limits cellular stress and cytotoxicity caused by an accumulation of misfolded ER proteins (1, 2). ERAD occurs through the ubiquitin proteasome pathway, wherein ER-localized ubiquitin ligases covalently modify substrates by attaching multiple copies of the protein ubiquitin, thus tagging them for degradation by cytosolic 26S proteasome (3-5).In Saccharomyces cerevisiae, the highly conserved HRD (HMGCoA † reductase degradation) pathway degrades a variety of ERAD substrates, including misfolded luminal proteins (ERAD-L substrates) such as CPY* and integral membrane proteins (ERAD-M substrates) such as Hmg2 (6, 7). Briefly, ERAD-L substrates are ubiquitinated by the HRD complex, which includes the ubiquitin RING-H2 ligase Hrd1, complex members Hrd3, Usa1, and Der1, and luminal factors implicated in substrate selection (3,(8)(9)(10)(11). Conversely, ERAD-M substrates require only Hrd1 and Hrd3 for in vivo degradation (12, 13). Although Hrd1 functions as the core catalytic subunit of the HRD E3 ligase, Hrd3's function has remained enigmatic. Both Hrd1 and Hrd3 are highly conserved, and Hrd1 is rate limiting for degradation of misfolded substrates (3,12,14,15). In yeast, the steady-state levels of Hrd1 strongly depend on Hrd3. At native levels of the HRD components, Hrd3 is required for Hrd1 stability: In a hrd3Δ, Hrd1 half-life drops to less than 15 min, resulting in very low levels (12). This concomitant loss of Hrd1 is due to rapid autodegradation, catalyzed by the RING domain of Hrd1 (16).Because of Hrd3's strong role in maintaining Hrd1 stability, it has remained unclear whether Hrd3 has any other independent ERAD functions. A ...

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“…Together, this complex is responsible for the degradation of a subset of misfolded proteins in the ER (11,12). Like its yeast counterpart Hrd3p (14), mammalian Sel1L is required for the stability of Hrd1 (20) and may both directly recruit substrates to Hrd1 (21) and regulate Hrd1 activity (22). Germline Sel1L or Hrd1 deficiency is embryonically lethal in mice (23,24), and acute global loss of Sel1L or Hrd1 in adult mice leads to premature death within 2 to 3 weeks (20,23), suggesting that Sel1L and Hrd1 are indispensable for both development and postnatal survival (11).…”

Section: Introductionmentioning

confidence: 99%

“…Like its yeast counterpart Hrd3p (14), mammalian Sel1L is required for the stability of Hrd1 (20) and may both directly recruit substrates to Hrd1 (21) and regulate Hrd1 activity (22). Germline Sel1L or Hrd1 deficiency is embryonically lethal in mice (23,24), and acute global loss of Sel1L or Hrd1 in adult mice leads to premature death within 2 to 3 weeks (20,23), suggesting that Sel1L and Hrd1 are indispensable for both development and postnatal survival (11). Recent studies of cell type-specific Sel1L-Hrd1 deficiency in adipocytes (25,26), B cells (27), and colonic epithelium (21) have delineated the physiological importance of ERAD in these various tissues and identified several endogenous substrates (11), including IRE1α of the unfolded protein response (UPR) in many cell types (20); lipoprotein lipase and PGC1β in adipocytes (25,26); and pre-B cell receptor in developing B cells (27).…”

Section: Introductionmentioning

confidence: 99%