title: Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway.
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.
authors.affiliation: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, 18 Library Drive, Building 18T, Room 101, Bethesda, MD 20892, USA.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Neena S
authors.initials: NS
authors.lastname: Rane
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Garrison
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology*; D006023:Glycoproteins / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D021382:Protein Sorting Signals; D021381:Protein Transport; D013379:Substrate Specificity
chemical_list: D006023:Glycoproteins; D018832:Molecular Chaperones; D011328:Prions; D021382:Protein Sorting Signals