Document Type

Article

Publication Date

4-20-2011

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in EMBO Journal. Volume 30, Issue 8, April 2011, Pages 1634-1644. The published version is available at DOI: 10.1038/emboj.2011.62.Copyright © Nature Publishing Group.

Abstract

The forces that drive conversion of nascent protein to major histocompatibility complex (MHC) class I-restricted peptides remain unknown. We explored the fundamental property of overt hydrophobicity as such a driver. Relocation of a membrane glycoprotein to the cytosol via signal sequence ablation resulted in rapid processing of nascent protein not because of the misfolded luminal domain but because of the unembedded transmembrane (TM) domain, which serves as a dose-dependent degradation motif. Dislocation of the TM domain during the natural process of endoplasmic reticulum-associated degradation (ERAD) similarly accelerated peptide production, but in the context of markedly prolonged processing that included nonnascent species. These insights into intracellular proteolytic pathways and their selective contributions to MHC class I-restricted peptide supply, may point to new approaches in rational vaccine design.