SARM1, the executioner of axon degeneration, is an ADP-ribosyl transferase and autoMARylation negatively regulates its activation

Axon degeneration is a hallmark of nearly all neurodegenerative diseases. SARM1 plays a central role in this process by degrading NAD+ into nicotinamide and ADPR or cADPR. SARM1 also catalyzes a base exchange reaction between NAD+-phosphate (NADP+) and nicotinic acid (NA) to generate NAADP. These second messengers (i.e., ADPR, cADPR, and NAADP), and NAD+ consumption, are thought to drive axon degeneration. Herein, we identify a fourth reaction catalyzed by SARM1: mono-ADP-ribosylation (MARylation). Specifically, we show that SARM1 MARylates itself and other proteins with a catalytic efficiency (kcat/Km) higher than its NAD+ hydrolase activity. We further show that auto-MARylation promotes a phase transition and renders SARM1 responsive to regulation by NMN. Notably, endogenous SARM1 is MARylated at mitochondria, suggesting that MARylation may regulate SARM1 localization. Together, these findings uncover new regulatory mechanisms and expand the known signaling functions of SARM1. SignificanceSARM1 is an NAD+ hydrolase that executes axon degeneration in myriad neurodegenerative diseases. In addition to NAD+ hydrolysis, SARM1 catalyzes NAD+ cyclization and a base exchange reaction with NADP+ and nicotinic acid. These studies show that SARM1 also catalyzes the transfer of single ADPR moieties to proteins, including itself. Notably, we show that this auto-modification regulates SARM1 activity, allowing the protein to respond to NMN and to permit the phase transition. We also show that endogenous SARM1 is modified at the mitochondria, suggesting that this post-translational modification regulates SARM1 subcellular localization. These findings offer valuable mechanistic insights into SARM1 regulation that will ultimately inform the development of inhibitors targeting SARM1 for neurodegenerative diseases.