TY - JOUR
T1 - Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch
AU - Meng, Qingcai
AU - Cai, Chunmei
AU - Sun, Tingzhe
AU - Wang, Qianliang
AU - Xie, Weihong
AU - Wang, Rongfu
AU - Cui, Jun
N1 - Funding Information:
This work was supported by the National Key Basic Research Program of China (grants 2014CB910800 and 2015CB859800), the National Natural Science Foundation of China (grants 31370869, 31522018, and 31400714), Guangdong Natural Science Funds for Distinguished Young Scholar (grant S2013050014772), and the Guangdong Innovative Research Team Program (grant 2011Y035). T. Sun. was partially supported by the Anhui Provincial Natural Science Foundation (grant 1408085QC50).
Publisher Copyright:
© 2015 Meng et al.
PY - 2015
Y1 - 2015
N2 - NLRC5 is an important regulator in innate immune responses. However, the ability of NLRC5 to inhibit NF-κB activation is controversial in different cell types. How dynamic modification of NLRC5 shapes NF-κB signaling remains unknown. We demonstrated that NLRC5 undergoes robust ubiquitination by TRAF2/6 after lipopolysaccharide treatment, which leads to dissociation of the NLRC5-IκB kinase complex. Experimental and mathematical analyses revealed that the K63- linked ubiquitination of NLRC5 at lysine 1,178 generates a coherent feedforward loop to further sensitize NF-κB activation. Meanwhile, we found USP14 specifically removes the polyubiquitin chains from NLRC5 to enhance NLRC5-mediated inhibition of NF-κB signaling. Furthermore, we found that different cell types may exhibit different sensitivities to NF-κB activation in response to NLRC5 ablation, possibly as a result of the various intrinsic levels of deubiquitinases and NLRC5. This might partially reconcile controversial studies and explain why NLRC5 exhibits diverse inhibitory efficiencies. Collectively, our results provide the regulatory mechanisms of reversible NLRC5 ubiquitination and its role in the dynamic control of innate immunity.
AB - NLRC5 is an important regulator in innate immune responses. However, the ability of NLRC5 to inhibit NF-κB activation is controversial in different cell types. How dynamic modification of NLRC5 shapes NF-κB signaling remains unknown. We demonstrated that NLRC5 undergoes robust ubiquitination by TRAF2/6 after lipopolysaccharide treatment, which leads to dissociation of the NLRC5-IκB kinase complex. Experimental and mathematical analyses revealed that the K63- linked ubiquitination of NLRC5 at lysine 1,178 generates a coherent feedforward loop to further sensitize NF-κB activation. Meanwhile, we found USP14 specifically removes the polyubiquitin chains from NLRC5 to enhance NLRC5-mediated inhibition of NF-κB signaling. Furthermore, we found that different cell types may exhibit different sensitivities to NF-κB activation in response to NLRC5 ablation, possibly as a result of the various intrinsic levels of deubiquitinases and NLRC5. This might partially reconcile controversial studies and explain why NLRC5 exhibits diverse inhibitory efficiencies. Collectively, our results provide the regulatory mechanisms of reversible NLRC5 ubiquitination and its role in the dynamic control of innate immunity.
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U2 - 10.1083/jcb.201505091
DO - 10.1083/jcb.201505091
M3 - Article
C2 - 26620909
AN - SCOPUS:84959386443
SN - 0021-9525
VL - 211
SP - 1025
EP - 1040
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -