PINK1 Catalytic Activity is Regulated by Phosphorylation on Serines 228 and 402 [Signal Transduction]

December 19th, 2014 by Aerts, L., Craessaerts, K., De Strooper, B., Morais, V. A.

Mutations in the PINK1 gene cause early-onset recessive Parkinson's disease (PD). PINK1 is a mitochondria-targeted kinase that regulates multiple aspects of mitochondrial biology, from oxidative phosphorylation to mitochondrial clearance. PINK1 itself is also phosphorylated and this might be linked to the regulation of its multiple activities. Here, we systematically analyze four previously identified phosphorylation sites in PINK1 for their role in autophosphorylation, substrate phosphorylation and mitophagy. Our data indicate that two of these sites, S228 and S402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting the N-terminus has an inhibitory effect on phosphorylation. We furthermore establish that phosphorylation of these PINK1 residues regulates the phosphorylation of substrates Parkin and Ubiquitin. Especially S402 phosphorylation appears to be important for PINK1 function, as it is involved in Parkin recruitment and the induction of mitophagy. Finally we identify T313 as a residue that is critical for PINK1 catalytic activity, but in contrast to previous reports, we find no evidence that this activity is regulated by phosphorylation. These data clarify the regulation of PINK1 through multisite phosphorylation.