The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of TBK1 activation and recruitment of OPTN and NDP52 to promote mitophagy

By Jin-Mi Heo, A. Ordureau, J. Paulo, J. Rinehart, J. Harper. Molecules and Cells, 2015

803 citations recorded by the source corpus.

Damaged mitochondria are detrimental to cellular homeostasis. One mechanism for removal of damaged mitochondria involves the PINK1-PARKIN pathway, which poly-ubiquitylates damaged mitochondria to promote mitophagy. We report that assembly of ubiquitin chains on mitochondria triggers the recruitment of autophagy adaptors concomitantly with activation of the TBK1 protein kinase, which physically associates with OPTN, NDP52, and SQSTM1. Full TBK1 activation in HeLa cells requires OPTN and NDP52, and OPTN ubiquitin chain binding. In addition to the known role of S177 phosphorylation in OPTN on ATG8 recruitment, TBK1-dependent phosphorylation on S473 and S513 promotes ubiquitin chain binding in vitro as well as TBK1 activation, OPTN mitochondrial retention, and efficient mitophagy in vivo. These data reveal a self-reinforcing positive feedback mechanism that coordinates TBK1-dependent autophagy adaptor phosphorylation with the assembly of ubiquitin chains on mitochondria to facilitate efficient mitophagy. Analogous mechanisms may facilitate adaptor-protein mediated delivery of other types of cargo to autophagosomes.

Subfields: Epidemiology, Neurology, Parasitology

View Paper: https://www.semanticscholar.org/paper/d6fd6f0914248d55d768b5a1fc7b38f3c8d41638

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Citations in the corpus

• Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors. (2020, background): “In all these processes, an essential step is the phosphorylation of its LIR motif (S177) and UBAN domain (S473) by TBK1 [90,142,147,148].”
• Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. (2016, background): “Recent work has shown that Optineurin is phosphorylated by TRAF-associated NFkB activator (TANK)-binding kinase 1 (TBK1) during mitophagy and this enhances its binding to ubiquitin chains (discussed below) [44,47].”
• Molecular mechanisms and physiological functions of mitophagy (2021, positive): “TBK1 activity is required for efficient recruitment of OPTN and NDP52 to the ubiquitinated mitochondria (Heo et al , 2015) where TBK1 phosphorylates OPTN at Ser177 to increase LC3 binding affinity (Wild et al , 2011) and at Ser473 and Ser513 to further increase the binding of OPTN to ubiquitin…”
• Molecular definitions of autophagy and related processes (2017, neutral): “Moreover, considerable cross talk between the proteasome and chaperone-mediated autophagy (CMA, see below for a definition) has been described (Massey et al , 2006; Schneider et al , 2014), and cytosolic proteins bound to heat shock protein family A (Hsp70) member 8 (HSPA8), which serves as the main”
• The mitophagy pathway and its implications in human diseases (2023, background): “63,64 A pathogenic E478G mutation in UBAN domain makes OPTN less able to bind to ubiquitin, thereby inhibiting mitophagy.”
• Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation (2023, background): “TBK1-dependent autophagy adaptor phosphorylation with the assembly of ubiquitin chains on mitochondria to facilitate efficient mitophagy [29].”
• Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “MAP1LC3-I is further processed by the E1 enzyme ATG7 and then the E2 enzyme ATG3, finally resulting in the formation of phosphatidylethanolamine-conjugated MAP1LC3-II through the ATG12-ATG5-ATG16L1 system.”
• Atg8 family LC3/GABARAP proteins are crucial for autophagosome–lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation (2016, background): “For example, Nix-mediated mitophagy does not involve ubiquitin-binding autophagy receptors such as optineurin and NDP52 and critically depends on LIR-mediated interactions with Atg8s (Sandoval et al., 2008; Novak et al., 2010).”
• Mechanisms of Selective Autophagy (2016, positive): “The cargo receptor CALCOCO2/NDP52 acts during selective autophagy of intracellular bacteria and damaged mitochondria [61-65].”
• Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria (2016, background): “Among possible targets are mutated superoxide dismutase 1 (SOD1) (36), the RNA-processing TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), and mitochondria (13, 23).”