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.