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The HOG ( H igh  O smolarity  G lycerol response) pathway plays a central role in controlling stress response, ergosterol biosynthesis, virulence factor production, and differentiation of  Cryptococcus neoformans , which causes fatal fungal meningoencephalitis. Recent transcriptome analysis of the HOG pathway discovered a Hog1-regulated gene (CNAG_00130.2), encoding a putative protein kinase orthologous to Rck1/2 in  Saccharomyces cerevisiae  and Srk1 in  Schizosaccharomyces pombe . Its function is not known in  C. neoformans . The present study functionally characterized the role of Hrk1 in  C. neoformans . Northern blot analysis confirmed that  HRK1  expression depends on the Hog1 MAPK. Similar to the  hog1Δ  mutant, the  hrk1Δ  mutant exhibited almost complete resistance to fludioxonil, which triggers glycerol biosynthesis via the HOG pathway. Supporting this, the  hrk1Δ  mutant showed reduced intracellular glycerol accumulation and swollen cell morphology in response to fludioxonil, further suggesting that Hrk1 works downstream of the HOG pathway. However, Hrk1 also appeared to have Hog1-independent functions. Mutation of  HRK1  not only further increased osmosensitivity of the  hog1Δ mutant , but also suppressed increased azole-resistance of the  hog1Δ  mutant in an Erg11-independent manner. Furthermore, unlike the  hog1Δ  mutant, Hrk1 was not involved in capsule biosynthesis. Hrk1 was slightly involved in melanin production but dispensable for virulence of  C. neoformans . These findings suggest that Hrk1 plays both Hog1-dependent and –independent roles in stress and antifungal drug susceptibility and virulence factor production in  C. neoformans . Particularly, the finding that inhibition of Hrk1 substantially increases azole drug susceptibility provides a novel strategy for combination antifungal therapy.

Hrk1 Plays Both Hog1-Dependent and -Independent Roles in Controlling Stress Response and Antifungal Drug Resistance in Cryptococcus neoformans