NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer

Abstract

Mice deficient in the protein NLRC3 are highly prone to colitis and tumour development in the colon as NLRC3 suppresses the activation of mTOR signalling pathways that help drive tumorigenesis. Expression of the innate immune sensor NLRC3, a poorly characterized member of the NLR family of cytoplasmic sensors, is markedly reduced in tumour tissue isolated from patients with colorectal cancer, suggesting possible involvement in cancer biology. Here Thirumala-Devi Kanneganti and colleagues report that mice deficient in NLRC3 are highly prone to colitis and tumour development in the colon. They show that NLRC3 suppresses the activation of mTOR signalling pathways that help to drive tumorigenesis. NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases1. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis2,3,4,5,6,7,8,9. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains10,11. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues12, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell-derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.

Cite this article

Karki, R., Man, S., Malireddi, R. et al. NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer. Nature 540, 583–587 (2016). https://doi.org/10.1038/nature20597

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