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Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4039-44. doi: 10.1073/pnas.1523926113. Epub 2016 Mar 30.

Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria.

Author information

1
Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt, Germany;
2
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
3
Institute of Molecular Biology, 55128 Mainz, Germany;
4
Max F. Perutz Laboratories, Vienna Biocenter, University of Vienna, 1030 Vienna, Austria;
5
Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany;
6
Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt, Germany; Institute of Immunology, School of Medicine, University of Split, 21 000 Split, Croatia ivan.dikic@biochem2.de.

Abstract

Selective autophagy of damaged mitochondria requires autophagy receptors optineurin (OPTN), NDP52 (CALCOCO2), TAX1BP1, and p62 (SQSTM1) linking ubiquitinated cargo to autophagic membranes. By using quantitative proteomics, we show that Tank-binding kinase 1 (TBK1) phosphorylates all four receptors on several autophagy-relevant sites, including the ubiquitin- and LC3-binding domains of OPTN and p62/SQSTM1 as well as the SKICH domains of NDP52 and TAX1BP1. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria. TBK1 in turn phosphorylates OPTN's UBAN domain at S473, thereby expanding the binding capacity of OPTN to diverse Ub chains. In combination with phosphorylation of S177 and S513, this posttranslational modification promotes recruitment and retention of OPTN/TBK1 on ubiquitinated, damaged mitochondria. Moreover, phosphorylation of OPTN on S473 enables binding to pS65 Ub chains and is also implicated in PINK1-driven and Parkin-independent mitophagy. Thus, TBK1-mediated phosphorylation of autophagy receptors creates a signal amplification loop operating in selective autophagy of damaged mitochondria.

KEYWORDS:

OPTN; TBK1; mitophagy; phosphorylation; ubiquitin

PMID:
27035970
PMCID:
PMC4839414
DOI:
10.1073/pnas.1523926113
[Indexed for MEDLINE]
Free PMC Article

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