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In most model and pathogenic yeasts that proliferate by budding, including Saccharomyces cerevisiae and Candida albicans, core septin subunits such as Cdc3 and Cdc12 are essential and their loss results in lethal cytokinetic defects. In Cryptococcus neoformans, by contrast, deletion of CDC12 or CDC3 yields viable cells that grow normally under permissive conditions, raising the question of how this pathogen maintains cell integrity without a functional septin complex. To address this, we compared the transcriptomes of wild-type cells and a cdc12\u0394 mutant. The cdc12\u0394 strain showed a focused set of transcriptional changes, with induction of genes involved in cell wall remodeling, stress-dependent morphogenetic programs, and pathways that promote fitness under compromised cytoskeletal conditions. Genetic analysis of the most highly induced genes uncovered factors that contribute to proliferation in the absence of Cdc12, including a previously uncharacterized aspartic-type endopeptidase that exhibits a genetic interaction with the loss of septin function. These findings outline the compensatory circuitry that permits septin-independent growth in C. neoformans and help explain why this pathogen can tolerate the absence of the septin complex. This intrinsic plasticity highlights C. neoformans as a powerful comparative model for studying the evolution and function of septins.<\/jats:p>","DOI":"10.1093\/g3journal\/jkag240","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T08:43:26Z","timestamp":1787993006000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic determinants that permit growth without the core septin Cdc12 in\n                    <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1093","volume":"16","author":[{"given":"Piotr R","family":"Stempinski","sequence":"first","affiliation":[{"name":"Department of Genetics and Biochemistry, Eukaryotic Pathogens Innovation Center, Clemson University , Clemson, SC 29634 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2741-8899","authenticated-orcid":false,"given":"Hannah S","family":"Akahoho","sequence":"additional","affiliation":[{"name":"Department 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