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

Murata, Hitoshi; Khine, Cho Cho; Nishikawa, Akane; Yamamoto, Ken; Kinoshita, Rie; Sakaguchi, Masakiyo

doi:10.1074/jbc.ra118.004578

Cited by 69 publications

(60 citation statements)

References 41 publications

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“…In mock infected animals 16 transcripts were differentially regulated, 4 of which are involved in the mitochondrial electron transport chain – Ndufa3 and Ndufb3 (complex I), Uqcrh (complex III), and Atp5k (complex V), as well as a number of small and large ribosomal proteins, and an apoptosis-associated tyrosine kinase (Table V and Fig 7D). In agreement with this data, a recent report suggests a role for SARM1 in mitochondrial respiration (8).…”

Section: Resultssupporting

confidence: 90%

“…RNAseq in our CRISPR strains suggests loss of SARM1 expression leads to changes in expression of ribosomal, and mitochondrial electron transport chain genes. This is in agreement with a recent study showing that SARM1 phosphorylation regulates NAD+ cleavage leading to inhibition of mitochondrial respiration (8). Overall the data suggest that reevaluation of phenotypes described in SARM1-deficient strains will be important for understanding the function of SARM1 in different contexts.…”

Section: Discussionsupporting

confidence: 94%

“…Although the mechanism is not fully elucidated, SARM1 appears to be the master executioner in this cascade (4). Mechanistic and structural studies suggest that the SARM1 TIR domain possesses intrinsic NAD+ cleavage activity (5-7), which is regulated by JNK-mediated phosphorylation of Ser-548 leading to inhibition of mitochondrial respiration (8).…”

Section: Introductionmentioning

confidence: 99%

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Passenger mutations confound phenotypes of SARM1-deficient mice

Uccellini¹,

Bardina²,

Sánchez-Aparicio³

et al. 2019

Preprint

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AbstractThe Toll/IL-1R domain-containing adaptor protein SARM1 is expressed primarily in the brain, where it mediates axonal degeneration. Additional roles for SARM1 in a number of other processes including TLR-signaling, viral infection, chemokine expression, and expression of the proapoptotic protein XAF1 have also been described. Much of the supporting evidence for SARM1 function has been generated by comparing WT C57BL/6 (B6) mice to SARM1-deficient mice backcrossed to the B6 background. Here we show that the Sarm1 gene lies in a gene-rich region encompassing XAF1, and the MIP and MCP chemokine family loci among other genes. Because gene-targeting of SARM1-deficient strains was done with 129 ES cells and these genes are too close to segregate, they remain 129 in sequence. As this could account for phenotypes attributed to SARM1, we generated new knockout mouse strains on a pure B6 background using CRISPR. Experiments in these new strains confirmed the role of SARM1 in axonal degeneration and susceptibility to WNV infection, but not in susceptibility to VSV or LACV infection, or chemokine or Xaf1 expression. Notably, the Xaf1 gene shows sequence variation between B6 and 129, resulting in coding changes and novel splice variants. Given its known role in apoptosis, XAF1 variants may account for some phenotypes described in previously made SARM1-deficient strains. RNAseq in the new strains reveal changes in the mitochondrial electron transport chain and ribosomal proteins, suggesting possible downstream targets of SARM1. Re-evaluation of described phenotypes in these new strains will be critical for defining the function of SARM1.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Passenger mutations confound phenotypes of SARM1-deficient mice

Uccellini¹,

Bardina²,

Sánchez-Aparicio³

et al. 2019

Preprint

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“…Activation of SARM1 has been shown to promote phosphorylation of JNK to trigger neuronal immune response after axonal injury [56]. Moreover, phosphorylation of SARM1 by JNK regulates NAD + cleavage to inhibit mitochondrial respiration in response to oxidative stress [30]. Therefore, SARM1 may also be activated by JNK to promote further NAD + depletion (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of sterile alpha and armadillo motif (SARM1), which has intrinsic NAD + cleavage activity [22][23][24]. Beyond proteins that in uence NAD + levels, several other factors have been implicated in promoting Wallerian degeneration including death receptor 6 (DR6), calpain, Phr1 E3 ubiquitin ligase, dual leucine zipper kinase (DLK), c-jun n-terminal kinase (JNK), and axundead (Axed) [6,[25][26][27][28][29][30][31]. Whether these factors all converge on similar signaling hubs such as NAD + remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Regulation of degenerative spheroids after injury

Yan

Gamage

Cushman

et al. 2020

Preprint

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Background Neuronal injury leads to rapid, programmed disintegration of axons distal to the site of lesion. Much like other forms of axon degeneration ( e.g. developmental pruning, toxic insult from neurodegenerative disorder), Wallerian degeneration associated with injury is preceded by spheroid formation along axons. The mechanisms by which injury leads to formation of spheroids remains elusive. Methods Here, using wild-type and mutant neonatal mouse primary sympathetic neurons, immunostaining and calcium imaging, we investigate the roles of players previously implicated in the progression of Wallerian degeneration in injury-induced spheroid formation. Results We find that intra-axonal calcium flux is accompanied by actin-Rho dependent growth of calcium rich axonal spheroids that eventually rupture, releasing material to the extracellular space prior to catastrophic axon degeneration. Importantly, after injury, Sarm1 -/- and DR6 -/- , but not Wld s (excess NAD + ) neurons, are capable of forming spheroids that eventually rupture, releasing their contents to the extracellular space. Supplementation of exogenous NAD + or expressing WLD s suppresses Rho-dependent spheroid formation and degeneration in response to injury. Conclusions Taken together, our findings place Rho-actin and NAD + upstream of spheroid formation and may suggest that other mediators of degeneration, such as DR6 and SARM1, mediate post-spheroid rupture events that lead to catastrophic axon disassembly.

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Enzymatic and Endogenous Synthesis of Nad(p)‐derived Calcium‐mobilizing Messengers

Lee¹,

Zhao²

2022

Nucleic Acids in Medicinal Chemistry and Chemical Biology

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

Cited by 69 publications

References 41 publications

Passenger mutations confound phenotypes of SARM1-deficient mice

Passenger mutations confound phenotypes of SARM1-deficient mice

Regulation of degenerative spheroids after injury

Enzymatic and Endogenous Synthesis of Nad(p)‐derived Calcium‐mobilizing Messengers

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