{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wells KM"],"funding":["Defense Advanced Research Projects Agency","NICHD NIH HHS","NIAID NIH HHS","National Natural Science Foundation of China","National Institutes of Health","Bill and Melinda Gates Foundation","NIGMS NIH HHS","Texas A and M University","National Science Foundation"],"pagination":["e73625"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9119680"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11"],"pubmed_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."],"journal":["eLife"],"pubmed_title":["<i>Brucella</i> activates the host RIDD pathway to subvert BLOS1-directed immune defense."],"pmcid":["PMC9119680"],"funding_grant_id":["R01 HD084339","R21 GM132705","1R01AI141607-01A1","RHD084339","81371773","DBI1532188","NSF0854684","HR001118A0025-FoF-FP-006","R01 AI141607","R21 AI139738","1R21GM132705-01","R21AI139738-01A1","Clinical Science Translational Research Institute Pilot Grant CSTR2016-1"],"pubmed_authors":["Johnson CD","Zhang D","Zhang H","Ficht A","da Costa LF","Berghman LR","Wells KM","Liu Y","Martin CL","Metz R","Pandey A","Chang H","Patrick KL","Yang J","Skrobarczyk J","Feng X","He K","Song J","Sze SH","Qian X","Li X","Cabello A","Qin QM","de Figueiredo P","Gomez G","Leibowitz J","Ficht TA"],"additional_accession":[]},"is_claimable":false,"name":"<i>Brucella</i> activates the host RIDD pathway to subvert BLOS1-directed immune defense.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 May","modification":"2024-11-14T20:21:36.941Z","creation":"2022-07-11T17:20:56.204Z"},"accession":"S-EPMC9119680","cross_references":{"pubmed":["35587649"],"doi":["10.7554/eLife.73625"]}}