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EMBO Rep. 2018 May;19(5). pii: e45603. doi: 10.15252/embr.201745603. Epub 2018 Mar 8.

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

Author information

1
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
2
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK jan33@cam.ac.uk.

Abstract

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.

KEYWORDS:

ERAD ; MARCH6; TRC8; intramembrane proteolysis; protein quality control

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