Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson’s disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and therefore its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated. In this study, we demonstrate that the ubiquitin E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) promotes PINK1 ubiquitination and decreases its steady-state levels. Moreover, PINK1 levels were strongly reduced in HEK293 and SH-SY5Y cells exposed to the apoptosis-inducer staurosporine. Of note, we found that this reduction resulted from CHIP-mediated PINK1 ubiquitination. Accordingly, siRNA-mediated CHIP knockdown reduced susceptibility to staurosporine-induced cell death. Taken together, these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1’s cytoprotective effect during staurosporine-induced mammalian cell death. We propose that this PINK1 regulatory pathway might contribute to Parkinson’s disease pathogenesis.
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning Grant 2014M3C7A1064545 (to K. C. C.) and the Korea Healthcare Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare Grant HI17C0936 (to K. C. C.), Republic of Korea. This work was also supported in part by the NRF Grant 2015R1A2A2A01003080 (to K. C. C.) and by the Yonsei University Future-leading Research Initiative of 2015 Grant 2015–22-0055 (to K. C. C.). The authors declare that they have no conflicts of interest with the con-tents of this article.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology