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

TLDR

Selective mitophagy depends on kinases PINK1 and TBK1, ligase Parkin, and receptors such as OPTN, and because these proteins are linked to Parkinson’s disease and ALS/FTLD, understanding their functions is crucial. Quantitative proteomics revealed that TBK1 phosphorylates multiple autophagy receptors, and its constitutive interaction with OPTN—whose ubiquitin‑binding ability is essential—creates a signal‑amplification loop that recruits and retains TBK1/OPTN on ubiquitinated mitochondria.

Abstract

Significance Selective autophagy of damaged mitochondria (mitophagy) requires protein kinases PINK1 and TBK1, ubiquitin ligase Parkin, and autophagy receptors such as OPTN, driving ubiquitin-labeled mitochondria into autophagosomes. Because all proteins have been genetically linked to either Parkinson’s disease (PINK1 and Parkin) or amyotrophic lateral sclerosis and frontotemporal lobar degeneration (TBK1 and OPTN), it is of great interest to understand their physiological functions. By utilizing quantitative proteomics we show that TBK1 phosphorylates four receptors on several autophagy-relevant sites. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and activation on mitochondria. TBK1-mediated phosphorylation of OPTN creates a signal amplification loop through combining recruitment and retention of OPTN/TBK1 on ubiquitinated mitochondria.