<i>Brucella</i> 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 <i>Brucella</i>, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of <i>Bloc1s1</i> 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 <i>Bloc1s1</i> gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of <i>Brucella</i>-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant <i>Bloc1s1</i> 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 <i>Brucella</i> 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.