E3 Ligase FBXW7 Facilitates Mycobacterium Immune Evasion by Modulating TNF-α Expression.

Abstract

Tumor necrosis factor alpha (TNF-α) is a crucial factor in the control of Mycobacterium tuberculosis (Mtb) infection. Pathogenic mycobacteria can inhibit and/or regulate host cell TNF-α production in a variety of ways to evade antituberculosis (anti-TB) immunity as well as facilitate immune escape. However, the mechanisms by which TNF-α expression in host cells is modulated to the benefit of mycobacteria is still an interesting topic and needs further study. Here, we report that macrophages infected with Mycobacterium marinum (Mm)-a close relative of Mtb-upregulated the expression of E3 ubiquitin ligase FBXW7. Specific silencing FBXW7 with small interfering RNA (siRNA) significantly elevates TNF-α expression and eventually promotes the elimination of intracellular bacteria. In turn, overexpression of FBXW7 in Raw264.7 macrophages markedly decreased TNF-α production. Furthermore, partial inhibition of FBXW7 in an Mm-infected murine model significantly reduced TNF-α tissue content, alleviated tissue damage as well as reduced the bacterial load of mouse tails. Finally, FBXW7 could decrease TNF-α in a K63-linked ubiquitin signaling dependent manner. Taken together, our study uncovered a previously unknown role of FBXW7 in regulating TNF-α dynamics during mycobacterial infection, which provides new insights into understanding the role of FBXW7 in anti-tuberculosis immunity and its related clinical significance.

• Authors: Jingrui Song, Jin Chao, Xiaohong Hu, Xin Wen, Cairong Ding, Dan Li, Ding Zhang, Shanshan Han, Xiang Yu, Bo Yan, Zhu Jin, Yinhong Song, Jacqueline Gonzales, Laura E Via, Lu Zhang, Decheng Wang
• Journal: Frontiers in cellular and infection microbiology (Front Cell Infect Microbiol) Vol. 12 Pg. 851197 ( 2022) ISSN: 2235-2988 [Electronic] Switzerland
• PMID: 35651754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Song, Chao, Hu, Wen, Ding, Li, Zhang, Han, Yu, Yan, Jin, Song, Gonzales, Via, Zhang and Wang.

Chemical References

• F-Box-WD Repeat-Containing Protein 7
• Tumor Necrosis Factor-alpha
• Ubiquitin-Protein Ligases

Topics

• Animals
• F-Box-WD Repeat-Containing Protein 7 (genetics, metabolism)
• Immune Evasion
• Mice
• Mycobacterium marinum (genetics)
• Mycobacterium tuberculosis
• Tumor Necrosis Factor-alpha (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)