TRIM21 blocks DDX3X-driven stress granule formation during Mycobacterium tuberculosis infection via a non-canonical E3 ligase mechanism
- 1Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China
- 2Guangzhou Medical Research Institute of Infectious Diseases, Infectious Disease Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- 3Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, School of Medicine, Shenzhen, China
Abstract
Tripartite motif-containing 21 (TRIM21) is an E3 ubiquitin ligase that binds viral and host proteins to mediate antiviral defense. Its role in Mycobacterium tuberculosis (Mtb) infection, however, is unclear. Here, our analysis of human TB transcriptomic datasets showed that TRIM21 expression levels correlate with TB progression in human patients. We further demonstrated that TRIM21 deficiency suppresses Mtb growth in both macrophages and a murine model of tuberculosis (TB). Mechanistically, TRIM21 limits host resistance to Mtb through a non-canonical pathway distinct with its E3 ligase activity. It physically interacts with the RNA helicase DEAD-box helicase family member DDX3X and disrupts phase separation dynamics required for stress granule (SG) assembly. Impaired SG formation compromises innate immune responses, thereby facilitating intracellular bacterial growth and creating a permissive cellular environment for Mtb growth. Consistent with these genetic findings, pharmacological inhibition of TRIM21 restricted Mtb growth in experimental macrophage and murine models. Together, these findings uncover a non-canonical role of TRIM21 in Mtb infection and highlight its potential as a therapeutic target for host-directed therapy against TB. Author summary: Tuberculosis (TB) remains one of the world’s most serious infectious diseases, and better treatments are urgently needed to improve outcomes for patients. Because host immunity plays a critical role in controlling Mycobacterium tuberculosis (Mtb) infection, host-directed therapy (HDT), which enhances protective host responses, has emerged as a promising complementary approach.
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BibTeX
@article{xu2026trim21,
title = {{TRIM21 blocks DDX3X-driven stress granule formation during Mycobacterium tuberculosis infection via a non-canonical E3 ligase mechanism}},
author = {Ruiyao Xu and Mengru Lu and Gaoyan Wang and Ximeng Zhang and Yuxing Huang and Yu Wang and Qing Yu and Yaxuan Wang and Dan Chen and Yunlong Hu and Chenyan Shi and Yi Cai and Li Fu and Xinchun Chen and Youchao Dai},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014553},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014553},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TRIM21 blocks DDX3X-driven stress granule formation during Mycobacterium tuberculosis infection via a non-canonical E3 ligase mechanism
AU - Ruiyao Xu
AU - Mengru Lu
AU - Gaoyan Wang
AU - Ximeng Zhang
AU - Yuxing Huang
AU - Yu Wang
AU - Qing Yu
AU - Yaxuan Wang
AU - Dan Chen
AU - Yunlong Hu
AU - Chenyan Shi
AU - Yi Cai
AU - Li Fu
AU - Xinchun Chen
AU - Youchao Dai
PY - 2026
DA - 2026/09/08
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014553
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014553
AB - Tripartite motif-containing 21 (TRIM21) is an E3 ubiquitin ligase that binds viral and host proteins to mediate antiviral defense. Its role in Mycobacterium tuberculosis (Mtb) infection, however, is unclear. Here, our analysis of human TB transcriptomic datasets showed that TRIM21 expression levels correlate with TB progression in human patients. We further demonstrated that TRIM21 deficiency suppresses Mtb growth in both macrophages and a murine model of tuberculosis (TB). Mechanistically, TRIM21 limits host resistance to Mtb through a non-canonical pathway distinct with its E3 ligase activity. It physically interacts with the RNA helicase DEAD-box helicase family member DDX3X and disrupts phase separation dynamics required for stress granule (SG) assembly. Impaired SG formation compromises innate immune responses, thereby facilitating intracellular bacterial growth and creating a permissive cellular environment for Mtb growth. Consistent with these genetic findings, pharmacological inhibition of TRIM21 restricted Mtb growth in experimental macrophage and murine models. Together, these findings uncover a non-canonical role of TRIM21 in Mtb infection and highlight its potential as a therapeutic target for host-directed therapy against TB. Author summary: Tuberculosis (TB) remains one of the world’s most serious infectious diseases, and better treatments are urgently needed to improve outcomes for patients. Because host immunity plays a critical role in controlling Mycobacterium tuberculosis (Mtb) infection, host-directed therapy (HDT), which enhances protective host responses, has emerged as a promising complementary approach.
SN - 1553-7374
ER -