Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control.
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 approximately 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 approximately 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.
Qian
Shu-Bing
SB
Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0440, USA.
Princiotta
Michael F
MF
Bennink
Jack R
JR
Yewdell
Jonathan W
JW
D000818:Animals; D049452:Green Fluorescent Proteins / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007668:Kidney / Q000166:cytology; D008322:Mammals; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021381:Protein Transport; D012270:Ribosomes / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D050883:HSC70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease