Deubiquitination of SARM1 by USP13 Regulates SARM1 Activation and Axon Degeneration

Overview

Journal Life Med

Date 2025 Jan 28

PMID 39872893

Authors

Wenkai Yue

Kai Zhang

Mingsheng Jiang

Wenjing Long

Jihong Cui

Yunxia Li

Yaoyang Zhang

Ang Li

Yanshan Fang

Affiliations

Soon will be listed here.

Abstract

Sterile alpha and Toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is regarded as a key protein and a central executor of the self-destruction of injured axons. To identify novel molecular players and understand the mechanisms regulating SARM1 function, we investigated the interactome of SARM1 by proximity labeling and proteomic profiling. Among the SARM1-associated proteins, we uncovered that overexpression (OE) of ubiquitin-specific peptidase 13 (USP13) delayed injury-induced axon degeneration. OE of an enzyme-dead USP13 failed to protect injured axons, indicating that the deubiquitinase activity of USP13 was required for its axonal protective effect. Further investigation revealed that USP13 deubiquitinated SARM1, which increased the inhibitory interaction between the N-terminal armadillo repeat motif (ARM) and C-terminal Toll/interleukin-1 receptor (TIR) domains of the SARM1 protein, thereby suppressing SARM1 activation in axon injury. Collectively, these findings suggest that increase of USP13 activity enhances the self-inhibition of SARM1, which may provide a strategy to mitigate axon degeneration in injury and disease.

References

Essuman K, Summers D, Sasaki Y, Mao X, DiAntonio A, Milbrandt J . The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017; 93(6):1334-1343.e5. PMC: 6284238. DOI: 10.1016/j.neuron.2017.02.022. View

Osterloh J, Yang J, Rooney T, Fox A, Adalbert R, Powell E . dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012; 337(6093):481-4. PMC: 5225956. DOI: 10.1126/science.1223899. View

Milde S, Gilley J, Coleman M . Subcellular localization determines the stability and axon protective capacity of axon survival factor Nmnat2. PLoS Biol. 2013; 11(4):e1001539. PMC: 3627647. DOI: 10.1371/journal.pbio.1001539. View

Gerdts J, Summers D, Sasaki Y, DiAntonio A, Milbrandt J . Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013; 33(33):13569-80. PMC: 3742939. DOI: 10.1523/JNEUROSCI.1197-13.2013. View

Wang Q, Sun Z, Xia W, Sun L, Du Y, Zhang Y . Role of USP13 in physiology and diseases. Front Mol Biosci. 2022; 9:977122. PMC: 9515447. DOI: 10.3389/fmolb.2022.977122. View

Summers D, Gibson D, DiAntonio A, Milbrandt J . SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A. 2016; 113(41):E6271-E6280. PMC: 5068253. DOI: 10.1073/pnas.1601506113. View

Yang J, Wu Z, Renier N, Simon D, Uryu K, Park D . Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell. 2015; 160(1-2):161-76. PMC: 4306654. DOI: 10.1016/j.cell.2014.11.053. View

Wakatsuki S, Saitoh F, Araki T . ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol. 2011; 13(12):1415-23. DOI: 10.1038/ncb2373. View

Gerdts J, Summers D, Milbrandt J, DiAntonio A . Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron. 2016; 89(3):449-60. PMC: 4742785. DOI: 10.1016/j.neuron.2015.12.023. View

10.

Shi Y, Kerry P, Nanson J, Bosanac T, Sasaki Y, Krauss R . Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Mol Cell. 2022; 82(9):1643-1659.e10. PMC: 9188649. DOI: 10.1016/j.molcel.2022.03.007. View

11.

Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein M, Geiger T . The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016; 13(9):731-40. DOI: 10.1038/nmeth.3901. View

12.

Kim Y, Zhou P, Qian L, Chuang J, Lee J, Li C . MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med. 2007; 204(9):2063-74. PMC: 2118693. DOI: 10.1084/jem.20070868. View

13.

Jiang Y, Liu T, Lee C, Chang Q, Yang J, Zhang Z . The NAD-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature. 2020; 588(7839):658-663. DOI: 10.1038/s41586-020-2862-z. View

14.

Sun X, Duan Y, Qin C, Li J, Duan G, Deng X . Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy. Cell Death Dis. 2018; 9(10):953. PMC: 6148241. DOI: 10.1038/s41419-018-1022-y. View

15.

Yamagishi Y, Tessier-Lavigne M . An Atypical SCF-like Ubiquitin Ligase Complex Promotes Wallerian Degeneration through Regulation of Axonal Nmnat2. Cell Rep. 2016; 17(3):774-782. PMC: 5075525. DOI: 10.1016/j.celrep.2016.09.043. View

16.

Desbois M, Crawley O, Evans P, Baker S, Masuho I, Yasuda R . PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2. J Biol Chem. 2018; 293(36):13897-13909. PMC: 6130950. DOI: 10.1074/jbc.RA118.002176. View

17.

Xue T, Sun Q, Zhang Y, Wu X, Shen H, Li X . Phosphorylation at S548 as a Functional Switch of Sterile Alpha and TIR Motif-Containing 1 in Cerebral Ischemia/Reperfusion Injury in Rats. Mol Neurobiol. 2020; 58(2):453-469. DOI: 10.1007/s12035-020-02132-9. View

18.

Coleman M, Hoke A . Programmed axon degeneration: from mouse to mechanism to medicine. Nat Rev Neurosci. 2020; 21(4):183-196. PMC: 8926152. DOI: 10.1038/s41583-020-0269-3. View

19.

Li X, Yang G, Zhang W, Qin B, Ye Z, Shi H . USP13: Multiple Functions and Target Inhibition. Front Cell Dev Biol. 2022; 10:875124. PMC: 9014248. DOI: 10.3389/fcell.2022.875124. View

20.

Wakatsuki S, Tokunaga S, Shibata M, Araki T . GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration. J Cell Biol. 2017; 216(2):477-493. PMC: 5294778. DOI: 10.1083/jcb.201606020. View