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J. Biol. Chem., Vol. 281, Issue 1, 392-400, January 6, 2006

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Characterization of Rapidly Degraded Polypeptides in Mammalian Cells Reveals a Novel Layer of Nascent Protein Quality Control^*

From the Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0440

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 major histocompatibility complex class I molecules. Here we provide evidence that 75% of RDPs are degraded by the standard ubiquitin 26 S proteasome system and that their degradation is regulated by modulating Hsc70 activity in cells. Surprisingly, the remaining 25% of RDPs are degraded without ubiquitylation by 20 S proteasomes independently of 19 S regulators 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. 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 26 S proteasome pathway.

Received for publication, June 18, 2005 , and in revised form, October 7, 2005.

^* This work was supported by funding through the NIAID, National Institutes of Health intramural program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Rm. 211, Bldg. 4, 4 Center Dr., Bethesda, MD 20892-0440. Tel.: 301-402-4602; Fax: 301-480-4117; E-mail: jyewdell{at}nih.gov.

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