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J Cell Biol. 2015 Dec 7;211(5):1025-40. doi: 10.1083/jcb.201505091. Epub 2015 Nov 30.

Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch.

Author information

1
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
2
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China.
3
School of Life Sciences, AnQing Normal University, AnQing 246011, China cuij5@mail.sysu.edu.cn confucian007@126.com rwang3@tmhs.org.
4
Houston Methodist Research Institute, Houston, TX 77030 cuij5@mail.sysu.edu.cn confucian007@126.com rwang3@tmhs.org.
5
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510275, China cuij5@mail.sysu.edu.cn confucian007@126.com rwang3@tmhs.org.

Abstract

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.

PMID:
26620909
PMCID:
PMC4674279
DOI:
10.1083/jcb.201505091
[Indexed for MEDLINE]
Free PMC Article

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