Quantitative proteomics reveal a feed-forward model for mitochondrial PARKIN translocation and UB chain synthesis

By A. Ordureau, Shireen A. Sarraf, David M. Duda, Jin-Mi Heo, Mark P. Jedrychowski, Vladislav O. Sviderskiy, Jennifer L. Olszewski, J. T. Koerber, T. Xie, S. Beausoleil and 4 more. Molecules and Cells, 2014

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Phosphorylation is often used to promote protein ubiquitylation, yet we rarely understand quantitatively how ligase activation and ubiquitin (UB) chain assembly are integrated with phospho-regulation. Here we employ quantitative proteomics and live-cell imaging to dissect individual steps in the PINK1 kinase-PARKIN UB ligase mitochondrial control pathway disrupted in Parkinson’s Disease. PINK1 plays a dual role by phosphorylating PARKIN on its UB-like domain and poly-UB chains on mitochondria. PARKIN activation by PINK1 produces canonical and non-canonical UB chains on mitochondria, and PARKIN-dependent chain assembly is required for accumulation of poly-phospho-UB (poly-p-UB) on mitochondria. In vitro, PINK1 directly activates PARKIN’s ability to assemble canonical and non-canonical UB chains, and promotes association of PARKIN with both p-UB and poly-p-UB. Our data reveal a feed-forward mechanism that explains how PINK1 phosphorylation of both PARKIN and poly-UB chains synthesized by PARKIN drives a program of PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3fb65f65e2c14bd9d2bad43d4310e3a5d61c53ed

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Citations in the corpus

The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “K48- and K63-linked chains than K6- and K-11, whereas purified Parkin produced more noncanonical chain linkages than K48and K63-linked chains (Ordureau et al., 2014).”
Insights in Post-Translational Modifications: Ubiquitin and SUMO (2022, background): “One of the most studied is the essential role of the PARKIN E3 ligase and its function in regulating mitophagy by atypical K6 linkages [69,70].”
The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of TBK1 activation and recruitment of OPTN and NDP52 to promote mitophagy (2015, methodology): “Although linear chains are found in only very low abundance on depolarized mitochondria (Ordureau et al., 2014; Cunningham et al., 2015), we found, as expected (Gleason et al.”
Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. (2016, background): “mitophagy [20].”
Molecular mechanisms and physiological functions of mitophagy (2021, positive): “This Parkin-catalyzed ubiq-uitylation then further drives PINK1-catalyzed ubiquitin phosphorylation, leading to formation of a positive feedback loop for PINK1-and Parkin-catalyzed ubiquitylation (Ordureau et al , 2014; Okatsu et al , 2015).”
Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria (2016, background): “In fact, up to 20% of mitochondrial Ub is phosphorylated on S65 upon mitochondrial damage (7) and it is likely that Ub chains exposed to autophagy receptors consist of a mixture of pS65 Ub and unphosphorylated Ub.”