NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.
Stringent control of the NF-kappaB 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-kappaB-dependent responses by interacting with IKKalpha and IKKbeta 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-kappaB and its responsive genes, TNF-alpha 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-kappaB and type I interferon signaling pathways and suggest an important role for NLRC5 in homeostatic control of innate immunity.
Cui
Jun
J
Center for Cell and Gene Therapy, and Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Zhu
Liang
L
Xia
Xiaojun
X
Wang
Helen Y
HY
Legras
Xavier
X
Hong
Jun
J
Ji
Jiabing
J
Shen
Pingping
P
Zheng
Shu
S
Chen
Zhijian J
ZJ
Wang
Rong-Fu
RF
D000818:Animals; D003001:Cloning, Molecular; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D016328:NF-kappa B; C548042:NLRC5 protein, human; C549161:NLRC5 protein, mouse; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase; D053487:DEAD-box RNA Helicases