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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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Mycobacterium tuberculosis Rv3875 upregulates TRIM21 expression through the type I interferon/STAT1 pathway and
Ruiyao Xu1, Yuxing Huang2, Gaoyan Wang2
1Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China; Guangzhou Medical Research Institute of Infectious Diseases, Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Microbial Pathogenesis
|May 3, 2026
Summary
Mycobacterium tuberculosis uses the virulence factor Rv3875 to trigger iron release via TRIM21-mediated ferritinophagy, promoting bacterial survival within macrophages. This highlights a key pathway for tuberculosis pathogenesis.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Mycobacterium tuberculosis (Mtb) requires iron for intracellular growth within macrophages.
- Mtb upregulates tripartite motif-containing protein 21 (TRIM21) to induce NCOA4-mediated ferritinophagy, enhancing iron availability.
- The specific Mtb virulence factor and signaling pathway driving TRIM21 expression remained unknown.
Purpose of the Study:
- To identify the Mtb virulence factor responsible for TRIM21 upregulation.
- To elucidate the signaling pathway linking Mtb virulence to ferritinophagy.
- To understand the role of Rv3875 in Mtb pathogenesis.
Main Methods:
- Screening of Mtb secretory proteins to identify virulence factors.
- Macrophage stimulation assays with Mtb components.
- Analysis of type I interferon (IFN) signaling pathway activation.
- Assessment of TRIM21 expression and NCOA4-dependent ferritinophagy.
Main Results:
- The Mtb secretory protein Rv3875 was identified as a key virulence factor.
- Rv3875 activates the type I IFN signaling pathway, inducing IFN-β production.
- IFN-β subsequently upregulates TRIM21 expression in macrophages.
- Rv3875 utilizes the TRIM21-NCOA4 ferritinophagy axis to promote Mtb intracellular growth.
Conclusions:
- Rv3875 is a critical Mtb virulence factor that hijacks host ferritinophagy via the TRIM21-NCOA4 pathway.
- This mechanism enhances iron bioavailability, facilitating Mtb survival and growth.
- Targeting the Rv3875-TRIM21-NCOA4 axis represents a potential therapeutic strategy for tuberculosis.
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