Abstract
Terminally misfolded proteins that accumulate in the endoplasmic reticulum (ER) are dislocated and targeted for ubiquitin-dependent destruction by the proteasome. UBC6e is a tail-anchored E2 ubiquitin-conjugating enzyme that is part of a dislocation complex nucleated by the ER-resident protein SEL1L. Little is known about the turnover of tail-anchored ER proteins. We constructed a set of UBC6e transmembrane domain replacement mutants and found that the tail anchor of UBC6e is vital for its function, its stability, and its mode of membrane integration, the last step dependent on the ASNA1/TRC40 chaperone. We constructed a tail-anchored UBC6e variant that requires for its removal from the ER membrane not only YOD1 and p97, two cytosolic proteins involved in the extraction of ER transmembrane or luminal proteins, but also UBXD8, AUP1 and members of the Derlin family. Degradation of tail-anchored proteins thus relies on components that are also used in other aspects of protein quality control in the ER.
Highlights
The endoplasmic reticulum (ER) membrane is the main physical barrier that misfolded proteins must cross and is the arena where dislocation takes place
We identified UBC6e as part of a protein complex involved in dislocation of Class I major histocompatibility complex (MHC) products in cells that express the human cytomegalovirus (HCMV) immunoevasin US11 [11]
To characterize the mutant versions of UBC6e, we introduced them into U373 astrocytoma cells that stably express US11 and examined dislocation of Class I MHC heavy chains (HC) in a pulse-chase experiment
Summary
The ER membrane is the main physical barrier that misfolded proteins must cross and is the arena where dislocation takes place. We identified UBC6e as part of a protein complex involved in dislocation of Class I MHC products in cells that express the HCMV immunoevasin US11 [11].
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