title: Ubiquilins Chaperone and Triage Mitochondrial Membrane Proteins for Degradation.
abstract: We investigated how mitochondrial membrane proteins remain soluble in the cytosol until their delivery to mitochondria or degradation at the proteasome. We show that Ubiquilin family proteins bind transmembrane domains in the cytosol to prevent aggregation and temporarily allow opportunities for membrane targeting. Over time, Ubiquilins recruit an E3 ligase to ubiquitinate bound clients. The attached ubiquitin engages Ubiquilin's UBA domain, normally bound to an intramolecular UBL domain, and stabilizes the Ubiquilin-client complex. This conformational change precludes additional chances at membrane targeting for the client, while simultaneously freeing Ubiquilin's UBL domain for targeting to the proteasome. Loss of Ubiquilins by genetic ablation or sequestration in polyglutamine aggregates leads to accumulation of non-inserted mitochondrial membrane protein precursors. These findings define Ubiquilins as a family of chaperones for cytosolically exposed transmembrane domains and explain how they use ubiquitin to triage clients for degradation via coordinated intra- and intermolecular interactions.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Biology, Faculty of Science, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Itakura
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Eszter
authors.initials: E
authors.lastname: Zavodszky
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Sichen
authors.initials: S
authors.lastname: Shao
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57(th) Street, Chicago, IL 60637, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Wohlever
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57(th) Street, Chicago, IL 60637, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Keenan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: rhegde@mrc-lmb.cam.ac.uk.
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D064113:CRISPR-Cas Systems; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D066329:Protein Aggregates; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D034622:RNA Interference; D013329:Structure-Activity Relationship; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D010455:Peptides; D066329:Protein Aggregates; C486752:SYNJ2BP protein, human; C107792:UBQLN1 protein, human; C405662:UBQLN2 protein, human; D014452:Ubiquitins; C097188:polyglutamine; D044767:Ubiquitin-Protein Ligases