The Mechanistic Function of the NOD-like Receptor NLRX1 and SARM1 in Apoptosis Samuel Killackey1, Muhammed Aashiq Rahman2, and Stephen E. Girardin1,2 1Department of Laboratory Medicine and Pathobiology, University of Toronto; 2Department of Immunology, University of Toronto
NLRX1 is a member of the NOD-like family of intracellular receptors (NLRs). NLRs play critical roles in the detection of microbes and danger signals. Our group has shown that NLRX1 was the first NLR to localize to the mitochondrial matrix. Cells lacking NLRX1 show an increase in apoptotic cell death when treated with extrinsic apoptosis inducers, but a decreased sensitivity to intrinsic apoptotic pathways. In addition, when studying mouse models of colorectal cancer, mice lacking NLRX1 show a differential susceptibility to apoptosis and tumorigenesis depending on inflammation. While our current model proposes that NLRX1 controls the sensitivity to intrinsic versus extrinsic apoptotic signals, the mechanism of this differential sensitivity remains unknown. Several putative partners for NLRX1 have been proposed. Here we show that NLRX1 interacts with SARM1, a protein playing key roles in calcium-induced cell death and the promotion of Wallerian degeneration in neurons. Importantly, NLRX1 was shown to modulate apoptotic cell death through SARM1. Future studies will investigate the location of interaction, and possible upstream and downstream effectors that lead to these effects on apoptosis.
This work was funded by the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society (CCS).