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.