<p>by Yina Wang, Robert J. Tancer, Maggie Wear, Katrina M. Jackson, Yu Zhang, Kan Li, Jun Wang, Yong-Gui Gao, Kirsten Nielsen, Arturo Casadevall, Chaoyang Xue</p> Nutrient sensing and utilization are critical for microbes to adapt to their environment and evade predators. The encapsuled yeast <i>Cryptococcus neoformans</i> has a unique ability to sense and utilize the sugar inositol as both a signaling molecule and as a carbon source. This trait is advantageous not only in the natural environment but also to promote its pathogenesis, including invasion of the central nervous system. In this study, we have identified a novel inositol transporter-like receptor (transceptor) Itr4 that coordinates inositol and glucose metabolism by regulating inositol transporters (<i>ITR</i>s) and glucose sensor Hxs1. Itr4 binds inositol and regulates the function of other <i>ITR</i>s and its loss leads to a significant decrease in inositol uptake activity, resulting in a lack of mating, reduced capsule size, reduced blood–brain barrier (BBB) penetration, and virulence attenuation. Mutagenesis analysis of Itr4 protein identified an essential N-terminal tail and two amino acids, Q388 and Q389, as sites of functional importance. The <i>ITR4</i><sup>Q388A, Q389A</sup> allele showed a dominant phenotype with increased inositol uptake, enlarged capsule and significantly attenuated virulence. In summary, we identify a new <i>C. neoformans</i> inositol transceptor, Itr4, the first such example in eukaryotes, with novel regulatory roles in both inositol and glucose metabolism and fungal virulence.