Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including PTENinduced putative kinase 1 (PINK1), have been linked to early onset autosomal recessive forms of familial PD. PINK1 encodes a serine/threonine kinase, which phosphorylates several substrates and consequently leads to cell protection against apoptosis induced by various stresses. In addition, research has shown that inflammation largely contributes to the pathogenesis of PD, but the functional link between PINK1 and PD-linked neuroinflammation remains poorly understood. Therefore, in the present study, we investigated the functional role of PINK1 in interleukin (IL)-1β-mediated inflammatory signaling. We show that PINK1 specifically binds to TRAF6 and TAK1, and facilitates the autodimerization and autoubiquitination of TRAF6. PINK1 also enhances the association between TRAF6 and TAK1, phosphorylates TAK1, and stimulates polyubiquitination of TAK1. Furthermore, PINK1 leads to the potentiation of IL-1β-mediated NF-jB activity and cytokine production. These findings suggest that PINK1 positively regulates two key molecules, TRAF6 and TAK1, in the IL-1β-mediated signaling pathway, consequently upregulating their downstream inflammatory events.
Bibliographical noteFunding Information:
We thank J. Chung and G. Takaesu for providing plasmids. We are also grateful to G. Takaesu for providing 293 IL-1RI cells and to J. Shen for PINK1−/− and +/+ MEFs. This study was supported by grants from the Brain Research Center of the 21st Century Frontier Research Program Technology (2009 K-001251 to K.C.C.) and from the Korea Science and Engineering Foundation (KOSEF) through the National Research Laboratory Program (2010-0018916 to K.C.C.) funded by the Ministry of Education, Science and Technology (MEST) of the Republic of Korea. This work was also partly supported by grants from KOSEF (2012-0000810 to K.C.C.) and from the Korea Health 21 R&D Project (A092004 and A111653 to K.C.C.), Ministry of Health, Welfare and Family Affairs.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Cellular and Molecular Neuroscience
- Cell Biology