ABSTRACT
Nucleotide-binding domain, leucine-rich-repeat–containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication in Nature, we identified NLRC3 as a negative regulator of PI3K–mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K–mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K–mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K–AKT targets FoxO3a and FoxO1 in the colon of Nlrc3−/− mice, suggesting that additional signaling pathways contribute to increased cellular proliferation. Moreover, NLRC3 suppresses colorectal tumorigenesis by promoting cellular apoptosis. Genes encoding intestinal stem cell markers BMI1 and OLFM4 are upregulated in the colon of Nlrc3−/− mice. Herein, we discuss recent findings and explore mechanisms through which NLRC3 regulates PI3K–mTOR signaling. Our studies highlight the therapeutic potential of modulating NLRC3 to prevent and treat cancer.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank scientific editing department at St. Jude for their comments and suggestions.
Funding
Work from our laboratory is supported by the US National Institutes of Health (AI101935, AI124346, AR056296, and CA163507 to T.D.K.) and ALSAC (to T.D.K.).
Author contributions
R.K. and T.D.K. conceptualized the study; R.K. and R.K.S.M. designed the methodology; R.K., R.K.S.M., and Q.Z. performed the experiments; R.K., R.K.S.M., and Q.Z. conducted the analysis; R.K. and T.D.K. wrote the original draft of the manuscript; R.K.S.M. and Q.Z. reviewed and edited the manuscript; and T.D.K. provided the resources and supervised the study.