NLRC5 Negatively Regulates the NF-κB and Type I Interferon Signaling Pathways

Stringent control of the NF-κB and type I interferon signaling pathways is critical to effective host immune responses, yet the molecular mechanisms that negatively regulate these pathways are poorly understood. Here, we show that NLRC5, a member of the highly conserved NOD-like protein family, can...

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Bibliographic Details
Published in:Cell 2010-04, Vol.141 (3), p.483-496
Main Authors: Cui, Jun, Zhu, Liang, Xia, Xiaojun, Wang, Helen Y., Legras, Xavier, Hong, Jun, Ji, Jiabing, Shen, Pingping, Zheng, Shu, Chen, Zhijian J., Wang, Rong-Fu
Format: Article
Language:English
Subjects:
CELLIMMUNO
IKK protein
MOLIMMUNO
SIGNALING
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Summary:Stringent control of the NF-κB and type I interferon signaling pathways is critical to effective host immune responses, yet the molecular mechanisms that negatively regulate these pathways are poorly understood. Here, we show that NLRC5, a member of the highly conserved NOD-like protein family, can inhibit the IKK complex and RIG-I/MDA5 function. NLRC5 inhibited NF-κB-dependent responses by interacting with IKKα and IKKβ and blocking their phosphorylation. It also interacted with RIG-I and MDA5, but not with MAVS, to inhibit RLR-mediated type I interferon responses. Consistent with these observations, NLRC5-specific siRNA knockdown not only enhanced the activation of NF-κB and its responsive genes, TNF-α and IL-6, but also promoted type I interferon signaling and antiviral immunity. Our findings identify NLRC5 as a negative regulator that blocks two central components of the NF-κB and type I interferon signaling pathways and suggest an important role for NLRC5 in homeostatic control of innate immunity. [Display omitted] ► NLRC5 is a negative regulator of NF-κB activation and inflammatory cytokine production ► NLRC5 interacts with IKKα/IKKβ and blocks their phosphorylation ► NLRC5 also inhibits RIG-I-like receptor-mediated type I interferon responses ► Knockdown of NLRC5 enhances innate cytokine responses and antiviral immunity
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2010.03.040