Hog1/p38 regulates the integrated stress response (ISR) and global transcriptomic changes in C. neoformans during oxidative stress

Cryptococcus neoformans is an opportunistic fungal pathogen that is responsible for an estimated 112,000 deaths per year. We studied the role of the Hog1/p38 and Gcn2 signal transduction pathways during adaptation of C. neoformans to oxidative stress, a physiologically relevant stressor during infection. Using a combination of molecular assays and RNA-sequencing analysis in Hog1-, Gcn2-and double-deleted mutants, we identify shared targets of these pathways, and investigate a negative feedback loop that regulates induction of the integrated stress response (ISR). We found that simultaneous loss of Hog1 and Gcn2 profoundly impacts the ability of C. neoformans to tolerate oxidative stress. We also show that Hog1 regulates induction of the ISR, and that the Hog1 and Gcn2 pathways converge on repression of abundant, pro-growth mRNA, a key step in translatome reprogramming. Our results establish Hog1 and Gcn2 as key regulators of the response to oxidative stress, and demonstrate that the interplay between these pathways is critical for ROS tolerance in C. neoformans . More broadly, our results demonstrate the extent to which signaling via Hog1/p38 and Gcn2 are linked, and point to extensive recalibration of the cellular signaling apparatus when one of these pathways is disrupted.