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

## TL;DR

This study shows that caspase-3 activates the SARM1 enzyme during apoptosis, linking two cell death pathways and offering new insights into neurodegenerative diseases.

## Contribution

The study reveals a novel mechanism where caspase-3 cleaves and activates SARM1, linking apoptosis to SARM1-dependent cell death.

## Key findings

- Caspase-3 cleaves SARM1 in its ARM domain, activating its NAD+ hydrolase activity during apoptosis.
- A knock-in mouse model was developed to study the role of caspase-3 cleavage of SARM1 in different cell types.
- SARM1 activation through cleavage is crucial for apoptosis in macrophages and T cells but not always in neurons.

## Abstract

Sterile alpha and HEAT/Armadillo motif containing 1 (SARM1), an NAD+ hydrolase, drives axon degeneration/cell death in injured axons and in many neurodegenerative disease models. SARM1 can be activated by sensing a rise in the nicotinamide mononucleotide (NMN)/NAD+ ratio in cells/axons but other activation mechanisms remain understudied. This study identifies a critical role of SARM1 in promoting apoptosis. During apoptosis, the key apoptotic protease caspase-3 cleaves SARM1 within its autoinhibitory armadillo repeats (ARM) domain, derepressing its intramolecular autoinhibition and activating its NAD+ hydrolase function. This study proposes a mechanism of SARM1 activation by caspase-3 cleavage and provides a knock-in mouse model that will help dissect the contribution of this mechanism of SARM1 activation in disease models.

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.