Fig 7.

Schematic representation of the complex MAPK pathways for sexual reproduction and CWI of C. neoformans. In the left side, the pheromone-responsive Cpk1 MAPK pathway is known to activate Cpk1, which is believed to phosphorylate the transcription factor Mat2 for facilitating mating. While both Cpk1 and its paralog, Cpk2, contribute to this process, Cpk1 appears to play a predominant role. Once activated, Mat2 influences the expression of MFα1, SXI1α/a, and ZNF2 and additionally modulates CPK2 expression. Beyond this, Cpk1 appears to transcriptionally control Mat2 through an unknown transcription factor. Furthermore, Mpk1 and Mpk2 cooperate, probably targeting a phosphatase, which results in Mat2 inactivation. In the right side, the Mpk1 and Mpk2 MAPKs play redundant and distinct roles in maintaining cell wall and membrane integrity. This regulatory mechanism bifurcates into an Mpk2-dependent stress response—predominantly governed by Mpk1 but also influenced by Mpk2—and an Mpk2-independent stress response exclusively controlled by Mpk1. Aspects of CWI, such as chitin composition and capsule production, seem to be co-regulated by Mpk1 and Mpk2, with Mpk1 playing a major role in the modulation. Phosphorylation of Mpk2 is regulated by MAP2K Mkk2 like that of Mpk1. However, interestingly, Mpk2 phosphorylation is regulated by MAP3K Ssk2 and Ste11, not by Bck1. In contrast, cell membrane stability and thermotolerance are seemingly dictated solely by Mpk1. Under high-temperature stress, only Mpk1 was phosphorylated, while under SDS treatment, both Mpk1 and Mpk2 were dephosphorylated. Despite their differences in phosphorylation in response to types of membrane stress, phenotypic analysis revealed that only Mpk1 is involved in maintaining cell membrane integrity. Proteins and signaling pathways previously established in their roles are denoted by gray circles and black lines. In contrast, new contributions of this paper to understanding the mating process are highlighted in red, findings related to CWI are highlighted in blue, and those concerning cell membrane integrity are highlighted in green.