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

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.