TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a

Abstract

Pyroptosis is a form of regulated cell death mediated by the gasdermin protein family. During virus infection, cell pyroptosis restricts viral replication. The mechanisms of the tripartite motif (TRIM) protein family and IFN-stimulated genes (ISGs) against viruses have been studied. The role of TRIMs and ISGs in pyroptosis remains unclear. In this study, we show that TRIM21 interacts with ISG12a in viral infection and facilitates its translocation into the mitochondria by promoting its ubiquitination, thereby causing caspase 3 activation. Gasdermin E (GSDME) is specifically cleaved by caspase 3 upon viral infection, releasing the GSDME N-terminal domain, perforating the cell membrane, and causing cell pyroptosis. Our study uncovers a new mechanism of TRIM21 and ISG12a in regulating virus-induced cell pyroptosis.

ISG12a promotes immunotherapy of HBV-associated hepatocellular carcinoma through blocking TRIM21/AKT/β-catenin/PD-L1 axis

“… 18 In our study of innate immunity, IFN-stimulated gene 12a (ISG12a) has been identified with great potential on inhibiting viral infection and malignances: promoting the innate immune response of host cells to newcastle disease virus (NDV) infection, 19 restricting the infection of hepatitis C virus (HCV), 20 enhancing anticancer immunity by inhibiting the Wnt/β-catenin signaling pathway, 21 and inducing pyroptosis in virus-infected cancer cells. 22 The antiviral and anticancer effects make ISG12a an innate immune effector. However, direct evidence for relationship between immune regulation of ISG12a and immune surveillance of NK cells in cancer is still lacking.…”

“…Meanwhile, our previous study reported that TRIM21 enhances the innate immune response to viral infection, 28 and TRIM21-ISG12a interaction mediates cell pyroptosis in viral infection. 22 Herein, the inhibitory effect of ISG12a and TRIM21 on p -AKT and PD-L1 was observed in HBV-infected HLCZ01 cells and HepG2.2.15 cells ( Figures 5 C and 5D). Notably, the suppression of ISG12a on K63-dependent ubiquitin modification of AKT was enhanced by TRIM21 in HBV-infected HLCZ01 and HEK293T cells ( Figures 5 E and S5 B), and Pearson correlation analysis revealed a similar expression profile between the transcript levels of ISG12a and TRIM21 in CAs of HBV-associated HCC ( r = 0.5864, p < 0.0001, n = 55) ( Figure S5 C).…”

Multiple Roles of TRIM21 in Virus Infection

“…During the infections of the above viruses, TRIM21 triggers the K27-linked polyubiquitination of MAVS, which leads to the interaction between TBK1 and MAVS, followed by enhancement of the IRF3-associated immune responses against virus infection [ 20 , 48 ]. The increase in TRIM21 during NDV infection induces the K6-linked polyubiquitination of ISG12a at lys69 residue through the interaction between the DII of ISG12a and the PRY/SPRY domain of TRIM21 [ 49 ]. The ubiquitinated ISG12a translocated into mitochondria and activated caspase 3, followed by cleavage of gasdermin-E (GSDME) and induction of cell pyroptosis by the N-terminal of GSDME [ 49 ].…”

“…The increase in TRIM21 during NDV infection induces the K6-linked polyubiquitination of ISG12a at lys69 residue through the interaction between the DII of ISG12a and the PRY/SPRY domain of TRIM21 [ 49 ]. The ubiquitinated ISG12a translocated into mitochondria and activated caspase 3, followed by cleavage of gasdermin-E (GSDME) and induction of cell pyroptosis by the N-terminal of GSDME [ 49 ].…”

A Interacting Model: How TRIM21 Orchestrates with Proteins in Intracellular Immunity

“…After Newcastle disease virus (NDV) infection, K6‐linked polyubiquitination of IFN‐stimulated genes 12a (ISG12a) was mediated by TRIM21 at lys69 residue of ISG12a's DII domain, then TRIM21 facilitated ISG12a translocation into the mitochondria, moving on to activate caspase9 and caspase3, ultimately stepping in cell pyroptosis. [ 104 ] Also in combating bacteria, mass spectrometry analyses showed that the translocated AnkB effector of the intravacuolar pathogen Legionella pneumophila was modified by TRIM21‐mediated K11‐linked polyubiquitination. [ 8 ] In inflammatory bowel diseases, prohibitin1 (PHB1) was reported to bind to TRIM21 as a way of promoting inflammatory response, yet it can be competitively impaired by lung and nasal epithelium clone 1 (LPLUNC1) [ 105 ] and estrogen receptor β (ERβ).…”