c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration

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...

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Published in:	The Journal of biological chemistry Vol. 293; no. 49; pp. 18933 - 18943
Main Authors:	Murata, Hitoshi, Khine, Cho Cho, Nishikawa, Akane, Yamamoto, Ken-ichi, Kinoshita, Rie, Sakaguchi, Masakiyo
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 07-12-2018 American Society for Biochemistry and Molecular Biology
Subjects:	Adenosine Triphosphate - metabolism Armadillo Domain Proteins - chemistry Armadillo Domain Proteins - metabolism Cell Biology 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 NAD cell death nicotinamide adenine dinucleotide (NAD) mitochondria SARM1 c-Jun N-terminal kinase (JNK) ATP
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Hospital of UM1, University of Medicine, Yangon 11131, Myanmar. Edited by John M. Denu
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.RA118.004578