Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 3301-3315 |
| Number of pages | 15 |
| Journal | Cellular and Molecular Life Sciences |
| Volume | 69 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 2012 Oct 1 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Cellular and Molecular Neuroscience
- Cell Biology
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PINK1 stimulates interleukin-1β-mediated inflammatory signaling via the positive regulation of TRAF6 and TAK1. / Lee, Hyun Jung; Jang, Sung Hee; Kim, Hyeyoung; Yoon, Joo Heon; Chung, Kwang Chul.
In: Cellular and Molecular Life Sciences, Vol. 69, No. 19, 01.10.2012, p. 3301-3315.Research output: Contribution to journal › Article
TY - JOUR
T1 - PINK1 stimulates interleukin-1β-mediated inflammatory signaling via the positive regulation of TRAF6 and TAK1
AU - Lee, Hyun Jung
AU - Jang, Sung Hee
AU - Kim, Hyeyoung
AU - Yoon, Joo Heon
AU - Chung, Kwang Chul
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866348798&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866348798&partnerID=8YFLogxK
U2 - 10.1007/s00018-012-1004-7
DO - 10.1007/s00018-012-1004-7
M3 - Article
C2 - 22643835
AN - SCOPUS:84866348798
VL - 69
SP - 3301
EP - 3315
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
SN - 1420-682X
IS - 19
ER -