Mycobacterium tuberculosis Rv3875 upregulates TRIM21 expression through the type I interferon/STAT1 pathway and promotes intracellular growth.

Mycobacterium tuberculosis (Mtb) has evolved multiple strategies to acquire iron within macrophages, promoting its intracellular growth. We previously demonstrated that Mtb upregulates tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase to initiate NCOA4-mediated ferritinophagy, enhancing iron bioavailability for bacterial survival. However, the specific virulence factor and underlying signaling pathway involved remain unclear. In this study, we show that TRIM21 upregulation requires stimulation by virulence factors derived from live Mtb. Through screening of Mtb secretory proteins, we identified Rv3875 as a key virulence factor that drives TRIM21 expression in macrophages. Mechanistically, Rv3875 activates the type I interferon (IFN) signaling pathway, inducing IFN-β production, which in turn upregulates TRIM21 expression. Functionally, Rv3875 exploits this TRIM21 induction to promote NCOA4-dependent ferritinophagy, thereby establishing an intracellular environment that facilitates bacterial growth. Collectively, our findings identify Rv3875 as a central virulence factor regulating the TRIM21-NCOA4 ferritinophagy axis and highlight this pathway as a critical mechanism underlying Mtb pathogenicity. By elucidating these host-pathogen interactions, this study provides a conceptual foundation for targeting the Rv3875-TRIM21-NCOA4 axis as a potential therapeutic strategy against tuberculosis.