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STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production and P53-Dependent Apoptosis

72 Pages Posted: 4 Feb 2019 Sneak Peek Status: Published

See all articles by Dapei Li

Dapei Li

Chinese Academy of Medical Sciences - Center for Systems Medicine

Rongsheng Wu

Chinese Academy of Medical Sciences - Center for Systems Medicine

Wen Guo

Chinese Academy of Medical Sciences - Center for Systems Medicine

Shengchuan Chen

Chinese Academy of Medical Sciences - Center for Systems Medicine

Chaohao Huang

Chinese Academy of Medical Sciences - Center for Systems Medicine

Jingfei Zhu

Chinese Academy of Medical Sciences - Center for Systems Medicine

Lifen Xie

Chinese Academy of Medical Sciences - Center for Systems Medicine

Zigang Qiao

Chinese Academy of Medical Sciences - Center for Systems Medicine

Jian Huang

Soochow University - Department of Emergency

Mentao Zhou

Wenzhou Medical University - Department of Surgery

Yanghua Qin

Second Military Medical University - Department of Laboratory Diagnosis

Feng Ma

Chinese Academy of Medical Sciences - Center for Systems Medicine

More...

Abstract

Gamma-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and p53-dependent apoptosis. However, it is still unclear how to negatively regulate IFI16 to avoid excessive IFN-I production and autoimmunity. Here we find that STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting E3 ligase TRIM21. We have also identified the key sites which lead to STING-mediated IFI16 ubiquitination and degradation. Comparing to IFI16-WT, higher level of viral DNA-triggered IFN-β was detected in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant resistant to degradation. In addition, overexpression of STING significantly reduces Ser392-phosphorylated p53 and apoptosis in WT U2OS cells rather than in IFI16-/- cells, suggesting that STING-mediated IFI16 degradation suppresses p53-dependent apoptosis, and thus may promote DNA virus-induced tumorigenesis. Our study has described that STING-mediated negative feedback regulation of IFI16 controls both IFN-I production and p53-dependent apoptosis.

Keywords: IFI16, STING, TIRM21, ubiquitin proteasome system, type I interferon, antiviral immunity, p53, apoptosis, tumorigenesis

Suggested Citation

Li, Dapei and Wu, Rongsheng and Guo, Wen and Chen, Shengchuan and Huang, Chaohao and Zhu, Jingfei and Xie, Lifen and Qiao, Zigang and Huang, Jian and Zhou, Mentao and Qin, Yanghua and Ma, Feng, STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production and P53-Dependent Apoptosis (February 1, 2019). Available at SSRN: https://ssrn.com/abstract=3327222 or http://dx.doi.org/10.2139/ssrn.3327222
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Dapei Li

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Rongsheng Wu

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Wen Guo

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Shengchuan Chen

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Chaohao Huang

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Jingfei Zhu

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Lifen Xie

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Zigang Qiao

Chinese Academy of Medical Sciences - Center for Systems Medicine

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

Jian Huang

Soochow University - Department of Emergency

No. 1 Shizi Street
Taipei, Jiangsu 215006
China

Mentao Zhou

Wenzhou Medical University - Department of Surgery

Zhejiang Province
China

Yanghua Qin

Second Military Medical University - Department of Laboratory Diagnosis

Shanghai Shi, 200433
China

Feng Ma (Contact Author)

Chinese Academy of Medical Sciences - Center for Systems Medicine ( email )

NO. 9, Dongdan Santiao
Beijing, Dongcheng District
China

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