A MARCH6 and IDOL E3 ubiquitin ligase circuit uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes

Loregger, Anke; Cook, Emma C. L.; Nelson, Jessica K.; Moeton, Martina; Sharpe, Laura J.; Engberg, Susanna; Karimova, Madina; Lambert, Gilles; Zelcer, Noam

doi:10.1016/j.atherosclerosis.2016.07.057

Cited by 8 publications

(6 citation statements)

References 12 publications

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“…The identification of overlapping roles for TRC8 and MARCH may explain seemingly contradictory reports regarding TRC8 and MARCH6 substrates. For example, TRC8 was initially implicated in the regulation of SREBP‐1/2 , but loss of MARCH6 was recently shown to increase SREBP‐1/2 signalling . Our identification of SREBP‐1/2 (Fig A) as a potential MARCH6/TRC8 substrate may reconcile these findings.…”

Section: Discussionsupporting

confidence: 56%

MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins

et al. 2018

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Misfolded or damaged proteins are typically targeted for destruction by proteasome‐mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome‐mediated degradation of the soluble misfolded reporter, mCherry‐CL1, involves two ER‐resident E3 ligases, MARCH6 and TRC8. mCherry‐CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells. To identify a more physiological correlate, we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail‐anchored protein heme oxygenase‐1 (HO‐1). These E3 ligases associate with the intramembrane cleaving signal peptide peptidase (SPP) and facilitate the degradation of HO‐1 following intramembrane proteolysis. Our results highlight how ER‐resident ligases may target the same substrates, but work independently of each other, to optimise the protein quality control of selected soluble and tail‐anchored proteins.

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Section: Discussionsupporting

confidence: 56%

MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins

et al. 2018

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“…The MARCH protein repertoire can dictate responses to antitumor Abs. Consistent with other MARCH substrates, both MET and CD98 are regulated by a specific subset of MARCH family members (15,16,21,22,(39)(40)(41). In this study, we report that MARCH-mediated ubiquitination of membrane proximal lysines is required for the antiproliferative effects of these Abs.…”

Section: Discussionsupporting

confidence: 83%

MARCH Proteins Mediate Responses to Antitumor Antibodies

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et al. 2020

The Journal of Immunology

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CD98, which is required for the rapid proliferation of both normal and cancer cells, and MET, the hepatocyte growth factor receptor, are potential targets for therapeutic antitumor Abs. In this study, we report that the antiproliferative activity of a prototype anti-CD98 Ab, UM7F8, is due to Ab-induced membrane-associated ring CH (MARCH) E3 ubiquitin ligase-mediated ubiquitination and downregulation of cell surface CD98. MARCH1-mediated ubiquitination of CD98 is required for UM7F8's capacity to reduce CD98 surface expression and its capacity to inhibit the proliferation of murine T cells. Similarly, CD98 ubiquitination is required for UM7F8's capacity to block the colony-forming ability of murine leukemia-initiating cells. To test the potential generality of the paradigm that MARCH E3 ligases can mediate the antiproliferative response to antitumor Abs, we examined the potential effects of MARCH proteins on responses to emibetuzumab, an anti-MET Ab currently in clinical trials for various cancers. We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs.

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“…The I1061T NPC1 mutant has been described to accumulate in the ER lumen and to be degraded by two independent pathways functioning in a complementary fashion . It is degraded in part by ER‐phagy in a FAM134B‐ and autophagy‐dependent process; in part, it is triaged through ERAD by the proteasome via MARCH6, an E3 ubiquitin ligase involved in the control of cholesterol homoeostasis .…”

Section: The ‘Er‐phagy’ Pathwaymentioning

confidence: 99%

Emerging lysosomal pathways for quality control at the endoplasmic reticulum

2019

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Protein misfolding occurring in the endoplasmic reticulum (ER) might eventually lead to aggregation and cellular distress, and is a primary pathogenic mechanism in multiple human disorders. Mammals have developed evolutionary‐conserved quality control mechanisms at the level of the ER. The best characterized is the ER‐associated degradation (ERAD) pathway, through which misfolded proteins translocate from the ER to the cytosol and are subsequently proteasomally degraded. However, increasing evidence indicates that additional quality control mechanisms apply for misfolded ER clients that are not eligible for ERAD. This review focuses on the alternative, ERAD‐independent, mechanisms of clearance of misfolded polypeptides from the ER. These processes, collectively referred to as ER‐to‐lysosome–associated degradation, involve ER‐phagy, microautophagy or vesicular transport. The identification of the underlying molecular mechanisms is particularly important for developing new therapeutic approaches for human diseases associated with protein aggregate formation.

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A MARCH6 and IDOL E3 ubiquitin ligase circuit uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes

Cited by 8 publications

References 12 publications

MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins

MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins

MARCH Proteins Mediate Responses to Antitumor Antibodies

Emerging lysosomal pathways for quality control at the endoplasmic reticulum

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