title: TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation.
abstract: Selective autophagy adaptor proteins, including p62/SQSTM1, play pivotal roles in the targeted degradation of ubiquitinated proteins or organelles through the autophagy-lysosome system. However, how autophagy adaptors promote the autophagosomal engulfment of selected substrates is poorly understood. Here, we show that p62 phosphorylation at S403 is required for the efficient autophagosomal engulfment of polyubiquitinated mitochondria during Parkin-dependent mitophagy. p62 is able to interact with Parkin-recruited mitochondria without S403 phosphorylation under mitophagy-inducing conditions, but those mitochondria are not enclosed by autophagosomes. Intriguingly, the S403 phosphorylation occurs only in the early period of mitochondrial depolarization. Optineurin and TANK-binding kinase 1 (TBK1) are transiently recruited to the polyubiquitinated mitochondria, and the activated TBK1 phosphorylates p62 at S403. TBK1 inhibitor, BX795, prevents the p62-mediated autophagosomal engulfment of Parkin-recruited mitochondria. Our results suggest that TBK1-mediated S403 phosphorylation regulates the efficient autophagosomal engulfment of ubiquitinated mitochondria as an immediate response to the mitochondrial depolarization.
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders and Laboratory for Structural Neuropathology and Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan and Core Research for Evolutionary Science and Technology (CREST), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan nnukina@juntendo.co.jp g-matsumoto@nagasaki-u.ac.jp.
authors.forename: Gen
authors.initials: G
authors.lastname: Matsumoto
authors.affiliation: Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan and.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shimogori
authors.affiliation: Department of Neurology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders and Laboratory for Structural Neuropathology and Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan and Core Research for Evolutionary Science and Technology (CREST), JST, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan nnukina@juntendo.co.jp g-matsumoto@nagasaki-u.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics; D010766:Phosphorylation; D025821:Polyubiquitin / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025821:Polyubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human