| Autor: |
Stefanovic-Barrett, Sandra, Dickson, Anna S, Burr, Stephen P, Williamson, James C, Lobb, Ian T, Van Den Boomen, Dick Jh, Lehner, Paul J, Nathan, James A |
| Přispěvatelé: |
Nathan, James A [0000-0002-0248-1632], Apollo - University of Cambridge Repository |
| Rok vydání: |
2018 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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