Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense
| Title: | Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense |
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| Authors: | Kelsey Michelle Wells, Kai He, Aseem Pandey, Ana Cabello, Dongmei Zhang, Jing Yang, Gabriel Gomez, Yue Liu, Haowu Chang, Xueqiang Li, Hao Zhang, Xuehuang Feng, Luciana Fachini da Costa, Richard Metz, Charles D Johnson, Cameron Lee Martin, Jill Skrobarczyk, Luc R Berghman, Kristin L Patrick, Julian Leibowitz, Allison Ficht, Sing-Hoi Sze, Jianxun Song, Xiaoning Qian, Qing-Ming Qin, Thomas A Ficht, Paul de Figueiredo |
| Source: | eLife, Vol 11 (2022) |
| Publisher Information: | eLife Sciences Publications Ltd, 2022. |
| Publication Year: | 2022 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | Brucella, coronavirus, regulated IRE1α-dependent decay (RIDD), BLOS1, Brucella-containing vacuoles/lysosomes (BCVs), intracellular parasitism, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | 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 Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/73625; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.73625 |
| Access URL: | https://doaj.org/article/d0a8cb3ad2ef4a8c88d27a290700c019 |
| Accession Number: | edsdoj.0a8cb3ad2ef4a8c88d27a290700c019 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.73625 |
| Published in: | eLife |
| Language: | English |