SQSTM1/p62 is a novel substrate of the Parkinson's disease kinase LRRK2 that activates its kinase domain and enhances neuronal toxicity
Jing Zhao1*, Alexia F. Kalogeropulou1*, Marc F. Bolliger1, Anna Memou2, Tyler P. Molitor1, Hardy Rideout2, and Mark R. Cookson3, R. Jeremy Nichols1 1The Parkinson's Institute and Clinical Center, Sunnyvale, California USA; 2Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 3National Institute of Aging, Bethesda, MD USA *Equal contribution
Autosomal dominant, missense mutations in the Leucine Rich Repeat protein Kinase 2 (LRRK2) gene are the most common genetic predisposition to develop Parkinson's disease (PD). We recently identified the signaling adapter protein SQSTM1/p62 as a novel endogenous interacting partner and substrate of LRRK2. Using mass spectrometry and phosphospecific antibodies, we found that LRRK2 phosphorylates p62 on Thr138 in vitro and in cells. We found that the pathogenic LRRK2 PD associated mutations [N1437H, R1441C/G/H, Y1699C, G2019S] increase phosphorylation of p62 similar to previously reported substrates. In structure-function analyses, we found that LRRK2 phosphorylation of p62 Thr138 is dependent on a functional p62 ubiquitin binding domain at its carboxy terminus. We also found that the amino terminus of LRRK2 is crucial for optimal phosphorylation of p62 in cells, similar to what has been observed for Rab7L1. p62 expression activates LRRK2 intrinsic kinase activity as revealed by pSer1292 and decreases pSer935, analogous the Rab7L1 substrate; this is mediated through the p62-ZZ domain. We have further explored the impacts of p62 on LRRK2 Golgi-localization. Co-expression of p62 with LRRK2 G2019S increases the neurotoxicity of this mutation in primary neurons, in a manner dependent on Thr138. p62 is an additional novel substrate of LRRK2 that regulates its toxic biology, reveals novel signaling nodes and can be used as a pharmacodynamic marker for LRRK2 kinase activity.
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