Damaged mitochondria are flagged by ubiquitin (Ub) chains conjugated to proteins at the mitochondrial outer membrane (MOM) in a PINK1/PRKN-dependent manner. The conjugated Ub chains are recognized by cargo receptors such as optineurin (OPTN, also called FIP2 or NRP) tethering damaged mitochondria to components of the autophagy machinery promoting selective autophagy of mitochondria (mitophagy) (Onishi M et al., 2021; Goodall EA et al., 2022; Adriaenssens E et al., 2022).
OPTN directly interacts with TANK-binding kinase 1 (TBK1) (Morton S et al., 2008; Mankouri J et al., 2010; Gleason CE et al., 2011; Heo JM et al., 2015; Li F et al., 2016). TBK1 phosphorylates OPTN at S177, S473 or S513 enhancing the polyUb-binding function of OPTN, that primarily binds to M1- and K63-linked polyUb chains (Richter B et al., 2016; Li F et al., 2018). TBK1-mediated phosphorylation of OPTN at S473 has been shown to broaden the binding specificity of OPTN to other polyUb chains including K48-linked (Li F et al., 2018). The roles of OPTN and TBK1 in selective autophagy are critical for maintaining cellular homeostasis, and dysregulation of OPTN:TBK1-mediated autophagy has been implicated in disease pathogenesis (Wong YC & Holzbaur EL 2014; Harding O et al., 2021).
Interactions between OPTN and other proteins such as autophagy-related protein 9A (ATG9A) (Yamano K et al., 2020), myosin VI (MYO6), and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B or LC3) are implicated in autophagy.
This Reactome event shows TBK1-mediated phosphorylation of OPTN at MOM.
