Substrate-Specific Translocational Attenuation during ER Stress Defines a Pre-Emptive Quality Control Pathway

Sang Wook Kang, Neena S. Rane, Soo Jung Kim, Jennifer L. Garrison, Jack Taunton, Ramanujan S. Hegde

Research output: Contribution to journalArticlepeer-review

211 Scopus citations

Abstract

Eukaryotic proteins entering the secretory pathway are translocated into the ER by signal sequences that vary widely in primary structure. We now provide a functional rationale for this long-observed sequence diversity by demonstrating that differences among signals facilitate substrate-selective modulation of protein translocation. We find that during acute ER stress, translocation of secretory and membrane proteins is rapidly and transiently attenuated in a signal sequence-selective manner. Their cotranslational rerouting to the cytosol for degradation reduces the burden of misfolded substrates entering the ER and represents a pathway for pre-emptive quality control (pQC). Bypassing the pQC pathway for the prion protein increases its rate of aggregation in the ER lumen during prolonged stress and renders cells less capable of viable recovery. Conversely, pharmacologically augmenting pQC during ER stress proved protective. Thus, protein translocation is a physiologically regulated process that is utilized for pQC as part of the ER stress response.

Original languageEnglish (US)
Pages (from-to)999-1013
Number of pages15
JournalCell
Volume127
Issue number5
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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