The Cytoplasmic Sensor NLRC3 Inhibits mTOR Signaling in Tumors

The nucleotide-binding oligomerization domain-like receptor (NLR) CARD domain containing 3 (NLRC3) is a cytoplasmic sensor that negatively regulates host immune responses mediated by signaling pathways activated by Toll-like receptors and the cytosolic DNA sensor stimulator of interferon genes. While other NLR family members have been shown to drive or suppress tumorigenesis, it is unknown whether NLRC3 is involved in tumorigenesis. To ascertain the role of NLRC3 in carcinogenesis, Karki, Man, and colleagues evaluated murine models of carcinogen-induced and spontaneous colorectal tumors in wild-type (WT) and Nlrc3^−/− mice. Both carcinogen-treated Nlrc3^−/− mice and Apc^Min/+Nlrc3^−/− mice exhibited significant increases in tumor growth, colorectal dysplasia, and colonic inflammation compared to carcinogen-treated WT mice, suggesting that NLRC3 suppresses colorectal tumorigenesis. Similarly, Nlrc3^−/− mice exhibited increases in intestinal crypt proliferation and the ability to form intestinal organoids compared with WT mice. Assessment of cytokine production and bone marrow chimera studies revealed that NLRC3 mediated inflammation in an inflammasome-independent manner and that the tumor-inhibitory effect of NLRC3 was predominant in intestinal epithelial cells, respectively. Interrogation of the intracellular PI3K–AKT–mTOR signaling pathway, which is commonly upregulated in human cancers, revealed that Nlrc3^−/− mice exhibited increased phosphorylation of AKT at the mTOR phosphorylation site and the pyruvate dehydrogenase kinase 1 phosphorylation site, which activates mTOR signaling. Further, loss of NLRC3 resulted in the colocalization of mTOR with lysosomal-associated membrane protein 1, which mediates lysosomal mTOR signaling, and NLRC3 coimmunoprecipitated with the PI3K p85 regulatory subunit, decreased p85 phosphorylation, and inhibited the association of p85 with the PI3K p110α catalytic subunit. Additionally, the administration of a dual PI3K–mTOR inhibitor to Apc^Min/+Nlrc3^−/− mice and Apc^Min/+ mice reduced the tumor burden of Apc^Min/+Nlrc3^−/− mice to a level observed in Apc^Min/+ mice. Collectively, these results identify NLRC3 as a negative regulator of PI3K–mTOR signaling and characterize the potential inhibitory role of NLRC3 in colorectal tumorigenesis.

Karki R, Man SM, Malireddi RK, Kesavardhana S, Zhu Q, Burton AR, et al. NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer. Nature 2016;540:583–7.

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