title: Binding of SGTA to Rpn13 selectively modulates protein quality control.
abstract: Rpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show that the C-terminal region of Rpn13 binds to the tetratricopeptide repeat (TPR) domain of SGTA, a cytosolic factor implicated in the quality control of mislocalised membrane proteins (MLPs). The overexpression of SGTA results in a substantial increase in steady-state MLP levels, consistent with an effect on proteasomal degradation. However, this effect is strongly dependent upon the interaction of SGTA with the proteasomal component Rpn13. Hence, overexpression of the SGTA-binding region of Rpn13 or point mutations within the SGTA TPR domain both inhibit SGTA binding to the proteasome and substantially reduce MLP levels. These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle. We speculate that the binding of SGTA to Rpn13 enables specific polypeptides to escape proteasomal degradation and/or selectively modulates substrate degradation.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Pawel
authors.initials: P
authors.lastname: Leznicki
authors.affiliation: Department of Immunology and Medical Genetics, School of Medicine, University of Split, Soltanska 2, Split 21000, Croatia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Korac-Prlic
authors.affiliation: Institute of Biochemistry II, School of Medicine, Goethe University, Theodor-Stern-Kai 7, Frankfurt (Main) 60590, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kliza
authors.affiliation: Institute of Biochemistry II, School of Medicine, Goethe University, Theodor-Stern-Kai 7, Frankfurt (Main) 60590, Germany.
authors.forename: Koraljka
authors.initials: K
authors.lastname: Husnjak
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nyathi
authors.affiliation: Department of Immunology and Medical Genetics, School of Medicine, University of Split, Soltanska 2, Split 21000, Croatia Institute of Biochemistry II, School of Medicine, Goethe University, Theodor-Stern-Kai 7, Frankfurt (Main) 60590, Germany Buchmann Institute for Molecular Life Sciences, School of Medicine, Goethe University, Theodor-Stern-Kai 7, Frankfurt (Main) 60590, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK stephen.high@manchester.ac.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: High
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: C500781:ADRM1 protein, human; C411807:Adrm1 protein, mouse; C092009:BAG6 protein, human; C484266:Bag6 protein, mouse; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C114575:SGTA protein, human; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13
keywords: Bag6; Mislocalised proteins; Proteasomes; Protein degradation; TPR; Ubiquitylation