Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense
Abstract
The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding BLOS1, a protein that promotes endosome–lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus murine hepatitis virus also subverted the RIDD–BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 19, 2022
- Source ID
- 10.7554/elife.73625
Entities
People
- Allison Ficht
- Ana Cabello
- Aseem Pandey
- Cameron Lee Martin
- Charles D. Johnson
- Dongmei Zhang
- Gabriel Gomez
- Hao Zhang
- Haowu Chang
- Jianxun Song
- Jill Skrobarczyk
- Jing Yang
- Julian L. Leibowitz
- Kai He
- Kelsey Wells
- Kristin L Patrick
- Luc R Berghman
- Luciana Fachini Da Costa
- Paul de Figueiredo
- Qing-Ming Qin
- Richard Metz
- Sing-hoi Sze
- Thomas A. Ficht
- Xiaoning Qian
- Xuehuang Feng
- Xueqiang Li
- Yue Liu
Organizations
- Defense Advanced Research Projects Agency
- Gates Foundation
- Jilin University
- National Institutes of Health
- National Natural Science Foundation of China
- National Science Foundation
- Texas A&M Health Science Center
- Texas A&M University