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

Abstract

Nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) belong to a large family of cytoplasmic sensors which regulate an extraordinarily diverse range of biological functions. NLRs contribute to immunity against infectious diseases, however, dysregulation of their functional activity leads to the development of inflammatory diseases and autoimmunity 1. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis 2–8. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen of genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains 9,10. Expression of the gene encoding NLRC3 is drastically reduced in tumour tissues of patients with colorectal cancer compared with healthy tissues 11, highlighting an undefined potential function for this sensor in the development of cancer. Here, we found that mice lacking NLRC3 were hypersusceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 was most dominant in enterocytes, where NLRC3 suppressed activation of the mTOR signalling pathways and inhibited cellular proliferation and stem-cell-derived organoid formation. NLRC3 associated with phosphoinositide 3-kinases (PI3Ks) and blocked activation of the PI3K–dependent kinase AKT following engagement of growth factor receptors or TLR4. These findings unveiled a key role for NLRC3 as an inhibitor of the mTOR pathways mediating protection against colorectal cancer.

The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production

“…Despite the high relative expression of NLRC3 in T lymphocytes there have been no published in vivo phenotypes using mouse models. Phenotypic results have only been described in myeloid and epithelial/fibroblast cells (26, 48, 52). Therefore, we have focused our initial investigation using myeloid (THP1) and epithelial cells (HeLa), which express moderate to low levels of NLRC3 , but relatively high levels of IQGAP1 .…”

“…However, there is evidence that supports the model that NLR proteins respond cooperatively or redundantly to the same pathogen or that single NLRs can regulate disparate pathways that may be cell or species specific(25). For example, recent evidence has suggested that NLRC3 can also act as a negative regulator of the PI3K-mTOR pathway in epithelial cells, which is involved in colorectal carcinogenesis(26) as well as affecting the type I interferon and proinflammatory pathways. Likewise, NLRX1 has been shown to be involved in negatively regulating multiple tumorigenic pathways(27–29) as well as other inflammatory pathways(23, 28, 30–32).…”

Novel insights into microbiome in colitis and colorectal cancer

“…Karki et al demonstrated that NLRC3 suppresses tumorigenesis by inhibiting PI3K-AKT-mTOR signaling in Apc min/+ mice and AOM/DSS-treated WT mice (19). At the molecular level, NLRC3 interacts with PI3K to block AKT activation and binds to TRAF6 to attenuate TLR/NF-κB and mTOR activation (19, 20). …”

Phellinus linteus Mycelium Alleviates Myocardial Ischemia-Reperfusion Injury through Autophagic Regulation

“…Regulation of autophagy by mTOR-dependent pathways also could be adjusted by PI3K-AKT pathway (Karki et al, 2016). Hence, we observed the phosphorylation levels of PI3K and AKT (p-PI3K and p-AKT) in left heart ventricle (Supplementary Figures 1A,B).…”

“…In others researches, it was reported that mTOR manipulate the autophagy was not only regulated by AMPK but also by PI3K-AKT pathway (Karki et al, 2016). In physiological and pathological conditions, PI3K-AKT pathway was crucial to many aspects of cell growth and survival, and which was initiated by receptor tyrosine kinases (RTK) or G-protein–coupled receptors (GPCRs), which located at the cell surface and activated by many kinds of growth factors.…”