Abstract

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.

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Acknowledgements

We thank the Transgenic Gene Knockout Shared Resource at St. Jude Children’s Research Hospital (SJCRH) for assistance with knockout mouse generation. Images were acquired at the SJCRH Cell & Tissue Imaging Center, which is supported by SJCRH and NCI grant P30 CA021765-35. Work from our laboratory is supported by the US National Institutes of Health (grants AI101935, AI124346, AR056296 and CA163507 to T.-D.K.), ALSAC (to T.-D.K.), and the ExC306 Inflammation at Interfaces, the DFG SFB 877 B9 and DFG SFB1182 C2 projects (to P.R.). S.M.M. is supported by the R. G. Menzies Early Career Fellowship from the National Health and Medical Research Council of Australia.

Author information

Author notes

    • Rajendra Karki
    •  & Si Ming Man

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Rajendra Karki
    • , Si Ming Man
    • , R. K. Subbarao Malireddi
    • , Sannula Kesavardhana
    • , Qifan Zhu
    • , Amanda R. Burton
    • , Bhesh Raj Sharma
    • , Xiaopeng Qi
    • , Stephane Pelletier
    •  & Thirumala-Devi Kanneganti
  2. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA

    • Qifan Zhu
  3. Embryonic Stem Cell Laboratory, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Stephane Pelletier
  4. Animal Resources Center and the Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Peter Vogel
  5. Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany

    • Philip Rosenstiel

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Contributions

R.K., S.M.M. and T.-D.K. conceptualized the study; R.K., S.M.M., R.K.S.M. and S.K. designed the methodology; R.K., S.M.M., R.K.S.M., S.K., Q.Z., B.R.S., A.R.B., X.Q., S.P. and P.V. performed the experiments; R.K., S.M.M., R.K.S.M., S.K., Q.Z. and P.V. conducted the analysis; R.K., S.M.M. and T.-D.K. wrote the manuscript; P.R. and T.-D.K. provided resources; T.-D.K. provided overall supervision.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thirumala-Devi Kanneganti.

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https://doi.org/10.1038/nature20597

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