title: Secretory protein profiling reveals TNF-α inactivation by selective and promiscuous Sec61 modulators.
abstract: Cotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences profoundly affect substrate selectivity. Among the most sensitive substrates we identified is the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). Like all type II transmembrane proteins, TNF-α is targeted to the translocon by its membrane-spanning domain, indicating that a cleavable signal sequence is not strictly required for cotransin sensitivity. Our results thus reveal an unanticipated breadth of translocon substrates whose expression is inhibited by Sec61 modulators.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Maifeld
authors.forename: Andrew L
authors.initials: AL
authors.lastname: MacKinnon
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Garrison
authors.forename: Ajay
authors.initials: A
authors.lastname: Sharma
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Kunkel
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D000069816:SEC Translocation Channels; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C097977:HUN 7293; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D000069816:SEC Translocation Channels; D014409:Tumor Necrosis Factor-alpha; C502316:cotransin