NLRC3 negatively regulates PI3K–mTOR signaling to inhibit colon tumorigenesis.

  • Major finding: NLRC3 negatively regulates PI3K–mTOR signaling to inhibit colon tumorigenesis.

  • Mechanism: NLRC3 binds to the PI3K p85 subunit to prevent p85–p110α heterodimerization and repress p85 activity.

  • Impact: Restoration of NLRC3 function may be a therapeutic strategy for treating patients with colorectal cancer.

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 ApcMin/+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 ApcMin/+Nlrc3−/− mice and ApcMin/+ mice reduced the tumor burden of ApcMin/+Nlrc3−/− mice to a level observed in ApcMin/+ 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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