PINK1 stimulates interleukin-1β-mediated inflammatory signaling via the positive regulation of TRAF6 and TAK1.
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 PTEN-induced 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-κB 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 up-regulating their downstream inflammatory events.
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Seodaemun-gu, Republic of Korea.
Hyun Jung
HJ
Lee
Sung Hee
SH
Jang
Hyeyoung
H
Kim
Joo Heon
JH
Yoon
Kwang Chul
KC
Chung
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7; D000099202:PTEN-Induced Putative Kinase
D053583:Interleukin-1beta; D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011494:Protein Kinases; D048029:TNF Receptor-Associated Factor 6; D000099151:MAP Kinase Kinase Kinase 7; D000099202:PTEN-Induced Putative Kinase