Caspase-3 cleaves and activates the NADase SARM1 to promote apoptosis, linking two cell death mechanisms.

Two major mechanisms of axon degeneration have been identified. The first, a caspase-dependent apoptotic pathway, is a major mediator of developmental axon degeneration triggered by loss of trophic support. The second, a caspase-independent pathway mediated by the sterile alpha and HEAT/Armadillo motif containing 1 (SARM1) NADase, was found in studies of injury-induced Wallerian degeneration; it is also implicated in degeneration associated with traumatic brain injury, as well as some neurodegenerative diseases and neuropathies. Recent studies suggest that SARM1 functions as a metabolic sensor for the cellular nicotinamide mononucleotide/NAD+ ratio through its autoinhibitory armadillo repeats (ARM) domain. Here, we show a tight link between apoptotic and SARM1-dependent degeneration by demonstrating that SARM1 is activated during and contributes to apoptosis in neuroblastoma cells, macrophages, and T cells. Mechanistically, the key apoptotic protease caspase-3 cleaves SARM1 within its ARM domain, relieving its autoinhibition and activating its NAD+ hydrolase activity. Using a knock-in (KI) mouse model with a SARM1 mutation that prevents caspase-3 cleavage, we show that apoptosis promotion by SARM1 in macrophages and T cells requires its cleavage, whereas in neurons deprived of trophic support, activation of SARM1 occurs both with and without cleavage. Our study identifies a central role for SARM1 in apoptosis in some cells that is mediated by SARM1 activation through caspase-3 cleavage; it provides a model for dissecting the contributions of the two modes of SARM1 activation in different cellular contexts; and it has implications for the selection of ortho- versus allosteric SARM1 inhibitors for treating neurodegenerative diseases.