Editors' ChoiceImmunology

Keeping Balance in the Innate Immune System

Science Signaling  11 May 2010:
Vol. 3, Issue 121, pp. ec142
DOI: 10.1126/scisignal.3121ec142

Moderation is the key in a successful innate immune response, and excessive activation of inflammatory pathways can be as problematic as an inadequate protective response. Cui et al. explored the function of the NOD-like receptor NLRC5. NOD-like receptors are members of a protein family that includes detectors of viral nucleotides that activate the innate immune system. NLRC5’s function, however, appears to be as a negative regulator of innate immune signaling activated either by Toll-like receptors (another type of receptor that recognizes molecules derived from bacteria) or RIG-1–like receptors (which recognize viral RNAs). NLRC5 interacted with IKKα and IKKβ (the IκB kinases that promote signaling through the NF-κB transcription factor in response to Toll-like receptors or other signals). IKKs become activated when associated with the protein NEMO (NF-κB essential modulator), and the authors showed that NLRC5 competed with NEMO for binding to the IKKs. In the RIG-I pathway, NLRC5 was coimmunoprecipitated in a complex with RIG-I, and this blocked interaction of RIG-I with MAVS, an adaptor protein that links RIG-I with activators of NF-κB signaling. The physiological relevance of these findings was supported by experiments in which NLRC5 protein was depleted by siRNA in a mouse macrophage-derived cell line or a human acute monocytic leukemia cell line. Loss of NLRC5 enhanced accumulation of interferon-β mRNA in cells exposed to a viral stimulus. Depletion of NLRC5 in various mouse and human cells also rendered the cells resistant to viral infection. Expression of NLRC5 itself appeared to be regulated by NF-κB, indicating that NLRC5 may function as part of a negative feedback loop. Because of its role in modulating NF-κB–dependent transcription and production of type I interferon, the authors propose that NLRC5 is likely to be an important regulator of innate immune responses and may be a useful target to either enhance responses to microbial infection or combat diseases associated with excessive inflammation.

J. Cui, L. Zhu, X. Xia, H. Y. Wang, X. Legras, J. Hong, J. Ji, P. Shen, S. Zheng, Z. J. Chen, R.-F. Wang, NLRC5 negatively regulates the NF-κB and type I interferon signaling pathways. Cell 141, 483–496 (2010). [PubMed]