Deubiquitination of SARM1 by USP13 regulates SARM1 activation and axon degeneration.

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.