TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

Meixin Chen; Qingcai Meng; Yunfei Qin; Puping Liang; Peng Tan; Lian He; Yubin Zhou; Yongjun Chen; Junjiu Huang; Rong Fu Wang; Jun Cui

doi:10.1016/j.molcel.2016.08.025

TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

Meixin Chen, Qingcai Meng, Yunfei Qin, Puping Liang, Peng Tan, Lian He, Yubin Zhou, Yongjun Chen, Junjiu Huang, Rong Fu Wang, Jun Cui

Research output: Contribution to journal › Article › peer-review

258 Scopus citations

Abstract

Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14^−/− mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.

Original language	English (US)
Pages (from-to)	105-119
Number of pages	15
Journal	Molecular Cell
Volume	64
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2016.08.025
State	Published - Oct 6 2016

Keywords

TRIM14
USP14
autophagy
cGAS
p62
type I interferon (IFN) signaling

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2016.08.025

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@article{fea207150a6849918fc75208234bc069,

title = "TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses",

abstract = "Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14−/− mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.",

keywords = "TRIM14, USP14, autophagy, cGAS, p62, type I interferon (IFN) signaling",

author = "Meixin Chen and Qingcai Meng and Yunfei Qin and Puping Liang and Peng Tan and Lian He and Yubin Zhou and Yongjun Chen and Junjiu Huang and Wang, {Rong Fu} and Jun Cui",

note = "Funding Information: This work was supported by the National Key Basic Research Program of China (2015CB859800 and 2014CB910800), the National Natural Science Foundation of China (31370869, 31522018, 31371508, and 31601135), Guangdong Natural Science Funds for Distinguished Young Scholar (S2013050014772), the Fundamental Research Funds for the Central Universities (15lgjc02 and 16lgzd13), the Guangdong Innovative Research Team Program (2011Y035 and 201001Y0104687244), and the Science and Technology Planning Project of Guangdong Province (2015B020228002) and was in part supported by grants CA101795 and DA030338 from the NCI, NIDA, and NIH (to R.-F.W.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

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doi = "10.1016/j.molcel.2016.08.025",

language = "English (US)",

volume = "64",

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T1 - TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

AU - Chen, Meixin

AU - Meng, Qingcai

AU - Qin, Yunfei

AU - Liang, Puping

AU - Tan, Peng

AU - He, Lian

AU - Zhou, Yubin

AU - Chen, Yongjun

AU - Huang, Junjiu

AU - Wang, Rong Fu

AU - Cui, Jun

N1 - Funding Information: This work was supported by the National Key Basic Research Program of China (2015CB859800 and 2014CB910800), the National Natural Science Foundation of China (31370869, 31522018, 31371508, and 31601135), Guangdong Natural Science Funds for Distinguished Young Scholar (S2013050014772), the Fundamental Research Funds for the Central Universities (15lgjc02 and 16lgzd13), the Guangdong Innovative Research Team Program (2011Y035 and 201001Y0104687244), and the Science and Technology Planning Project of Guangdong Province (2015B020228002) and was in part supported by grants CA101795 and DA030338 from the NCI, NIDA, and NIH (to R.-F.W.). Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/10/6

Y1 - 2016/10/6

N2 - Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14−/− mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.

AB - Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14−/− mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.

KW - TRIM14

KW - USP14

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KW - cGAS

KW - p62

KW - type I interferon (IFN) signaling

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JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

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