RRC ID 54683
Author Murata H, Khine CC, Nishikawa A, Yamamoto KI, Kinoshita R, Sakaguchi M.
Title c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration.
Journal J Biol Chem
Abstract Mitochondrial dysfunction is a key pathological feature of many different types of neurodegenerative disease. Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) has been attracting much attention as an important molecule for inducing axonal degeneration and neuronal cell death by causing loss of NAD (NADH). However, it has remained unclear what exactly regulates the SARM1 activity. Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. Furthermore, neuronal cells derived from a familial Parkinson's disease (PD) patient showed a congenitally increased level of SARM1 phosphorylation compared with that in neuronal cells from a healthy person and were highly sensitive to oxidative stress. These results indicate that JNK-mediated phosphorylation of SARM1 at Ser-548 is a regulator of SARM1 leading to inhibition of mitochondrial respiration. These findings suggest that an abnormal regulation of SARM1 phosphorylation is involved in the pathogenesis of Parkinson's disease and possibly other neurodegenerative diseases.
Volume 293(49)
Pages 18933-18943
Published 2018-12-7
DOI 10.1074/jbc.RA118.004578
PII S0021-9258(20)31130-3
PMID 30333228
PMC PMC6295714
MeSH Adenosine Triphosphate / metabolism Armadillo Domain Proteins / chemistry Armadillo Domain Proteins / metabolism* Cell Line, Tumor Cell Respiration Cytoskeletal Proteins / chemistry Cytoskeletal Proteins / metabolism* HEK293 Cells Humans JNK Mitogen-Activated Protein Kinases / metabolism* Mitochondria / metabolism* NAD / metabolism NAD+ Nucleosidase / chemistry NAD+ Nucleosidase / metabolism* Oxidative Stress Phosphorylation Serine / chemistry
IF 4.106
Times Cited 13
Human and Animal Cells 201B7(HPS0063)