biostudies-literatureWells KMDefense Advanced Research Projects AgencyNICHD NIH HHSNIAID NIH HHSNational Natural Science Foundation of ChinaNational Institutes of HealthBill and Melinda Gates FoundationNIGMS NIH HHSTexas A and M UniversityNational Science Foundatione73625https://www.ebi.ac.uk/biostudies/studies/S-EPMC9119680biostudies-literatureUnknown11The 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.eLife<i>Brucella</i> activates the host RIDD pathway to subvert BLOS1-directed immune defense.PMC9119680R01 HD084339R21 GM1327051R01AI141607-01A1RHD08433981371773DBI1532188NSF0854684HR001118A0025-FoF-FP-006R01 AI141607R21 AI1397381R21GM132705-01R21AI139738-01A1Clinical Science Translational Research Institute Pilot Grant CSTR2016-1Johnson CDZhang DZhang HFicht Ada Costa LFBerghman LRWells KMLiu YMartin CLMetz RPandey AChang HPatrick KLYang JSkrobarczyk JFeng XHe KSong JSze SHQian XLi XCabello AQin QMde Figueiredo PGomez GLeibowitz JFicht TAfalse<i>Brucella</i> activates the host RIDD pathway to subvert BLOS1-directed immune defense.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.2022-01-01T00:00:00Z2022 May2024-11-14T20:21:36.941Z2022-07-11T17:20:56.204ZS-EPMC91196803558764910.7554/eLife.73625