Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

eLife

Qing-Ming Qin¹  Jing Yang²  Ana Cabello²  Xueqiang Li³  Xiaoning Qian⁴  Kai He⁵  Paul de Figueiredo⁵  Richard Metz⁶  Thomas A Ficht⁶  Sing-Hoi Sze⁶  Kelsey Michelle Wells⁶  Aseem Pandey⁶  Yue Liu⁶  Allison Ficht⁶  Dongmei Zhang⁶  Gabriel Gomez⁶  Jianxun Song⁷  Julian Leibowitz⁸  Kristin L Patrick⁸  Luc R Berghman⁸  Charles D Johnson⁹  Cameron Lee Martin^1,10  Jill Skrobarczyk^1,10  Luciana Fachini da Costa^1,11  Xuehuang Feng^1,11  Hao Zhang^1,11  Haowu Chang^1,12 

[1] Department of Biochemistry & Biophysics, Texas A&M University, College Station, United States;Department of Veterinary Pathobiology, Texas A&M University, College Station, United States;College of Plant Sciences, Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Jilin, China;Department of Computer Science and Engineering, Dwight Look College of Engineering, Texas A&M University, College Station, United States;Department of Electrical and Computer Engineering, Texas A&M University, College Station, United States;Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Bryan, United States;Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, United States;Department of Poultry Science, Texas A&M University, College Station, United States;Department of Veterinary Pathobiology, Texas A&M University, College Station, United States;Genomics and Bioinformatics Services, Texas A&M University, College Station, United States;Key Laboratory of Symbolic Computation and Knowledge Engineering, Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, China;Texas A&M Veterinary Medical Diagnostic Laboratory, Texas A&M University, College Station, United States;

关键词: Brucella;    coronavirus;    regulated IRE1α-dependent decay (RIDD);    BLOS1;    Brucella-containing vacuoles/lysosomes (BCVs);    intracellular parasitism;   

DOI  :  10.7554/eLife.73625

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown