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The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapies. Here, we explore a role for arrestin protein-mediated ubiquitination in stress response and pathogenesis in the pathogenic fungus\n              <jats:italic>Cryptococcus neoformans<\/jats:italic>\n              . In a previous study, we identified four arrestin-like proteins in\n              <jats:italic>C. neoformans<\/jats:italic>\n              and found that one of these is required for efficient membrane synthesis, likely by directing interaction between fatty acid synthases and the Rsp5 E3 ubiquitin ligase. Here, we further explore\n              <jats:italic>Cn<\/jats:italic>\n              Rsp5 function and determine that this single Ub ligase is absolutely required for pathogenesis and survival in the presence of cellular stress. Additionally, we show that a second arrestin-like protein, Ali2, similarly facilitates interaction between Rsp5 and some of its protein targets. Of the four postulated\n              <jats:italic>C. neoformans<\/jats:italic>\n              arrestin-like proteins, Ali2 appears to contribute the most to\n              <jats:italic>C. neoformans<\/jats:italic>\n              pathogenesis, likely by directing Rsp5 to pathogenesis-related ubiquitination targets. A proteomics-based differential ubiquitination screen revealed that several known cell surface proteins are ubiquitinated by Rsp5 and a subset also requires Ali2 for their ubiquitination. Rsp5-mediated ubiquitination alters the stability and the localization of these proteins. A loss of Rsp5-mediated ubiquitination results in cell wall defects that increase susceptibility to external stresses. These findings support a model in which arrestin-like proteins guide Rsp5 to ubiquitinate specific target proteins, some of which are required for survival during stress.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Microbial proteins involved in human infectious diseases often need to be modified by specific chemical additions to be fully functional. Here, we explore the role of a particular protein modification, ubiquitination, in infections due to the human fungal pathogen\n              <jats:italic>Cryptococcus neoformans<\/jats:italic>\n              . We identified a complex of proteins responsible for adding ubiquitin groups to fungal proteins, and this complex is required for virulence. These proteins are fungal specific and might be targets for novel anti-infection therapy.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00981-24","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T13:29:38Z","timestamp":1725542978000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress"],"prefix":"10.1128","volume":"15","author":[{"given":"Lukas M.","family":"du Plooy","sequence":"first","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2686-5726","authenticated-orcid":true,"given":"Calla L.","family":"Telzrow","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie B.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Probst","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Castro-Lopez","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA"},{"name":"Department of Biology, Texas Christian University, Fort Worth, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9290-3925","authenticated-orcid":true,"suffix":"Jr.","given":"Floyd L.","family":"Wormley","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA"},{"name":"Department of Biology, Texas Christian University, Fort Worth, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-627X","authenticated-orcid":true,"given":"J. 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