The Neglected Role of GSDMD C‐Terminal in Counteracting Type I Interferon Signaling

The GSDMD N-terminal fragment (GSDMD-NT)-mediated pyroptosis is extensively investigated. However, the role of the C-terminal domain of GSDMD (GSDMD-CT) is unexplored. This study demonstrates that GSDMD-CT acts as a negative regulator that suppresses IFN-I signaling during viral infection. Mechanistically, GSDMD-CT, released upon virus infection, interacts separately with retinoic acid-inducible gene I (RIG-I) and tank-binding kinase (TBK1), promoting the selective autophagic degradation of RIG-I via K48-linked polyubiquitination at Lys181 and TBK1 via K27-linked polyubiquitination at Lys487 by the E3 ligase TRIM28, which serves as a recognition signal for the cargo receptor NDP52 and TOLLIP, respectively. Moreover, the P414, Q416, and E459 amino sites are crucial for GSDMD-CT in counteracting antiviral responses. The findings highlight the role of GSDMD-CT in inhibiting antiviral immunity, providing insights into how viruses manipulate host defense mechanisms to enhance infection.

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Publication Details

Journal
Advanced Science
Published
2025-06-20
DOI
https://doi.org/10.1002/advs.202505255
Citations
1
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.80

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article

The Neglected Role of GSDMD C‐Terminal in Counteracting Type I Interferon Signaling

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1 citations
Advanced Science
interferon and immune responses
0.80
article

The Neglected Role of GSDMD C‐Terminal in Counteracting Type I Interferon Signaling

Suhui He, Xinyu Fu, Danyue Li, Yunjie Li, Qiao Jin, Zhiyong Yu, Weilv Xu, Fushan Shi, Yang Yang, Nan Chen, Weisong Shi, Yumeng Wang, Shiyang Liu, Jinxia Xu, Qian Lv, Xinyue Li, Zian Zhang, Yuanxiang Ge
article en
1 citations

Abstract

The GSDMD N-terminal fragment (GSDMD-NT)-mediated pyroptosis is extensively investigated. However, the role of the C-terminal domain of GSDMD (GSDMD-CT) is unexplored. This study demonstrates that GSDMD-CT acts as a negative regulator that suppresses IFN-I signaling during viral infection. Mechanistically, GSDMD-CT, released upon virus infection, interacts separately with retinoic acid-inducible gene I (RIG-I) and tank-binding kinase (TBK1), promoting the selective autophagic degradation of RIG-I via K48-linked polyubiquitination at Lys181 and TBK1 via K27-linked polyubiquitination at Lys487 by the E3 ligase TRIM28, which serves as a recognition signal for the cargo receptor NDP52 and TOLLIP, respectively. Moreover, the P414, Q416, and E459 amino sites are crucial for GSDMD-CT in counteracting antiviral responses. The findings highlight the role of GSDMD-CT in inhibiting antiviral immunity, providing insights into how viruses manipulate host defense mechanisms to enhance infection.

Advanced ScienceVol. 12(33)
Zhejiang A & F University (CN), Guangxi University (CN), Zhejiang Medicine (China) (CN), Zhejiang University of Technology (CN), Zhejiang University (CN)
National Natural Science Foundation of China, National Key Research and Development Program of China
Openalex Percentile: Top 27%
interferon and immune responses
0.80
DOIOpen Access PDFOpenAlex
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