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However, the host targets and their modulation by\n            <jats:italic>Brucella<\/jats:italic>\n            to facilitate the infection process remain obscure. Here, we report that the host ubiquitin-specific protease, USP8, negatively regulates the invasion of\n            <jats:italic>Brucella<\/jats:italic>\n            into macrophages through the plasma membrane receptor, CXCR4. Upon silencing or chemical inhibition of USP8, the membrane localization of the CXCR4 receptor was enriched, which augmented the invasion of\n            <jats:italic>Brucella<\/jats:italic>\n            into macrophages. Activation of USP8 through chemical inhibition of 14-3-3 protein affected the invasion of\n            <jats:italic>Brucella<\/jats:italic>\n            into macrophages.\n            <jats:italic>Brucella<\/jats:italic>\n            suppressed the expression of\n            <jats:italic>Usp8<\/jats:italic>\n            at its early stage of infection in the infected macrophages. Furthermore, we found that only live\n            <jats:italic>Brucella<\/jats:italic>\n            could negatively regulate the expression of\n            <jats:italic>Usp8<\/jats:italic>\n            , suggesting the role of secreted effector protein of\n            <jats:italic>Brucella<\/jats:italic>\n            in modulating the gene expression. Subsequent studies revealed that the\n            <jats:italic>Brucella<\/jats:italic>\n            effector protein, TIR-domain containing protein from\n            <jats:italic>Brucella<\/jats:italic>\n            , TcpB, plays a significant role in downregulating the expression of\n            <jats:italic>Usp8<\/jats:italic>\n            by targeting the cyclic-AMP response element-binding protein pathway. Treatment of mice with USP8 inhibitor resulted in enhanced survival of\n            <jats:italic>B. melitensis,<\/jats:italic>\n            whereas mice treated with CXCR4 or 14-3-3 antagonists showed a diminished bacterial load. Our experimental data demonstrate a novel role of\n            <jats:italic>Usp8<\/jats:italic>\n            in the host defense against microbial intrusion. The present study provides insights into the microbial subversion of host defenses, and this information may ultimately help to develop novel therapeutic interventions for infectious diseases.\n          <\/jats:p>","DOI":"10.1128\/iai.00289-23","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T14:00:49Z","timestamp":1704376849000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["<i>Brucella<\/i>\n            targets the host ubiquitin-specific protease,\n            <i>Usp8<\/i>\n            , through the effector protein, TcpB, for facilitating infection of macrophages"],"prefix":"10.1128","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0236-7643","authenticated-orcid":false,"given":"Kiranmai","family":"Joshi","sequence":"first","affiliation":[{"name":"Laboratory of Immunology and Microbial Pathogenesis, National Institute of Animal Biotechnology 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