The role of C. neoformans Hog1 and its effectors in translatome reprogramming

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Abstract Cryptococcus neoformans is an environmental fungus and opportunistic pathogen of people with compromised immune systems that causes an estimated 181,000 deaths annually. A key step in C. neoformans pathogenesis is adaptation to the host, which is mediated by several signal transduction pathways. Translatome reprogramming, changes in protein synthesis, is a key output of these signal transduction pathways that allows C. neoformans to rapidly fine-tune the stress response, and defects in this process are associated with reduced virulence. The Hog1 p38 MAP kinase (MAPK) module is one signaling module that mediates this process, though the mechanism and effectors by which Hog1 mediates reprogramming are unknown in C. neoformans. We propose to identify the molecular basis of Hog1 activation, and generate a high throughput characterization of its interactome. We also found that another translatome regulatory pathway, the Gcn2 pathway, is differentially regulated in hog1∆, and aim to evaluate the implications of this change in both translatome reprogramming as well as virulence. Thus, we hypothesize that Hog1 mediates changes to a broad interactome via its kinase activity, and that crosstalk with the Gcn2 pathway masks more severe defects in stress tolerance and virulence in hog1∆. We will be testing two specific aims: (1) Determine the mechanism by which Hog1 regulates stress responses in C. neoformans, and (2) Evaluate whether increased eIF2α phosphorylation compensates for loss of Hog1. This project is significant as it will elucidate the mechanism of reprogramming by Hog1, will identify effectors that could be targeted to inhibit this process, and will also examine a convergence point between two major signaling pathways. The overall goal of this research training plan is to equip the candidate with the necessary skills to answer these questions, and to provide them with relevant training to establish themselves as a successful academic investigator studying fungal pathogenesis and stress adaptation. These goals will be accomplished under the guidance of a sponsor and thesis advisory committee, with the help of training opportunities and equipment provided by the University at Buffalo, and through professional development opportunities at conferences and workshops.