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MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins
Author(s) -
StefanovicBarrett Sandra,
Dickson Anna S,
Burr Stephen P,
Williamson James C,
Lobb Ian T,
Boomen Dick JH,
Lehner Paul J,
Nathan James A
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745603
Subject(s) - library science , classics , medicine , history , computer science
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, mC herry‐ CL 1, involves two ER ‐resident E3 ligases, MARCH 6 and TRC 8. mC herry‐ CL 1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH 6/ TRC 8 cells. To identify a more physiological correlate, we used quantitative mass spectrometry and found that TRC 8 and MARCH 6 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.