Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover.
Nbr1, a ubiquitous kinase scaffold protein, contains a PB1, and a ubiquitin-associated (UBA) domain. We show here that the nbr1 UBA domain binds to lysine-48 and -63 linked polyubiquitin-B chains. Nbr1 also binds to the autophagic effector protein LC3-A via a novel binding site. Ubiquitin-binding, but not PB1-mediated p62/SQSTM1 interaction, is required to target nbr1 to LC3 and polyubiquitin-positive bodies. Nbr1 binds additionally to proteins implicated in ubiquitin-mediated protein turnover and vesicle trafficking: ubiquitin-specific peptidases USP8, and the endosomal transport regulator p14/Robld3. Nbr1 thus contributes to specific steps in protein turnover regulation disrupted in several hereditary human diseases.
King's College London, Department of Medical and Molecular Genetics, London, UK.
Sarah
S
Waters
Katie
K
Marchbank
Ellen
E
Solomon
Caroline
C
Whitehouse
Mathias
M
Gautel
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C549756:NBR1 protein, human; C486326:Nbr1 protein, mouse; D011506:Proteins; D011993:Recombinant Fusion Proteins; D025821:Polyubiquitin; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D008239:Lysine