Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control

doi:10.1074/jbc.M509126200

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Papers In Press, published online ahead of print November 1, 2005
J. Biol. Chem, 10.1074/jbc.M509126200
Submitted on August 18, 2005
Revised on October 7, 2005
Accepted on November 1, 2005

Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control

Shu-Bing Qian, Michael F. Princiotta, Jack R. Bennink, and Jonathan W. Yewdell

LVD, NIAID, NIH, Bethesda, MD 20906

Corresponding Author: jyewdell{at}nih.gov

Approximately 30% of polypeptides synthesized by mammalian cells are degraded with a half-life of <10 min by proteasomes. These rapidly degraded polypeptides (RDPs) constitute the bulk of proteasome substrates, and are the principal source of viral and self-peptide ligands for MHC class I molecules. Here we provide evidence that ~75% of RDPs are degraded by the standard ubiquitin 26S proteasome system, and that their degradation is regulated by modulating Hsc70 activity in cells. Surprisingly, the remaining ~25% of RDPs are degraded by 20S proteasomes without ubiquitylation and in a manner that is largely unaffected by modulating Hsc70 activity. This latter pathway is utilized for generating an antigenic peptide from viral defective ribosomal products (DRiPs). The dichotomy in the behavior of RDPs points to a novel quality control level for nascent proteins that is independent of the well established Hsc70-ubiquitin 26S proteasome pathway.

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