Msb2 Signaling Mucin Controls Activation of Cek1 Mitogen-Activated Protein Kinase in Candida albicans

Abstract

We have characterized the role that the Msb2 protein plays in the fungal pathogen Candida albicans by the use of mutants defective in the putative upstream components of the HOG pathway. Msb2, in cooperation with Sho1, controls the activation of the Cek1 mitogen-activated protein kinase under conditions that damage the cell wall, thus defining Msb2 as a signaling element of this pathway in the fungus. Candida albicans is an important human fungal pathogen, causing infections that may represent a serious health problem. This yeast is found as a commensal in certain body locations (mainly, the vagina and tractointestinal duct) but is able to gain access to different organs under conditions of altered host immune defenses causing severe diseases. Dimorphism, the environmentally regulated differentiation program that allows this fungus to switch between a yeast-like-form (unicellular) and a filamentous form (multicellular) (25,59,95), is considered to play an important-albeit not exclusive-role (27,51,79,82,94) in the virulence of this fungus. Therefore, besides its clinical importance as an opportunistic pathogen, this microbe represents an interesting model of morphogenesis and differentiation in lower eukaryotes.

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…The deletion of CST20, HST7, or CEK1 does not block filamentation induced by serum and does not dramatically affect the transcriptional profile of the yeast-to-hypha transition (241). Recently, Msb2 has been identified as a regulator of Cek1 (496). Along with Sho1, Msb2 activates Cek1, and the deletion of MSB2 leads to defects in hyphal invasion on solid media containing poor carbon sources or under conditions of hypoxia (496).…”

The Cek1‑mediated MAP kinase pathway regulates exposure of α‑1,2 and β‑1,2‑mannosides in the cell wall ofCandida albicansmodulating immune recognition

“…71 Hac1 further influences the synthesis of cell wall components and the transcription of genes involved in secretory and vesicle trafficking processes, at least under stress conditions. 70 The connection between tunicamycin and the Cek1 pathway is evidenced by the different regulation of KAR2 (encoding a ER stress chaperone 72,73 of the UPR pathway) between CAF2 (up-regulated) and cek1 (downregulated) in response to tunicamycin and the recent finding that Msb2, a signaling mucin essential for the activation of Cek1, 39 also regulates UPR-targets 74 under heat stress.…”

“…36,43 Activating stimuli of the Cek1 pathway include the resumption of growth from stationary phase 38 and tunicamycin. 39 We therefore analyzed the different transcriptional response upon tunicamycin (an N-glycosylation inhibitor) treatment in cek1 mutants compared to the wild type CAF2 in exponentially growing cells, with the aim of identifying putative targets of the route. We found 174 (up) and 130 (down) commonly regulated genes upon treatment in both strains (Fig.…”

“…In summary, we observed an important differential behavior between CAF2 and cek1 in response to the N-glycosylation inhibitor tunicamycin which mainly involved cell wall and stress related genes, in line with the previously reported cek1 susceptibility to cell wall inhibitors and glyco-stressors. 39,48 cek1 cell wall alterations are augmented upon treatment with tunicamycin Transmission electron microscopy (TEM) was used to analyze the appearance of the cell wall structure of cek1 mutants during exponential phase of growth. Contrasting to the morphology presented by wild type and cek1 strains in stationary phase of growth, 43 cek1 mutants showed, during an active phase of growth, a cell wall presenting a central layer with higher density than the wild type CAF2.…”

“…36,37 Signaling in this pathway is mediated through, at least, three upstream proteins: Sho1, Msb2 and Opy2. [38][39][40] This pathway is involved in morphogenesis and hyphal formation, 36 but it seems to be especially relevant for the adaptation to cell wall damage and glycosylation sensing. 41 Cek1 is phosphorylated in response to cell wall inhibitors and its activation is also regulated by quorum sensing and growth.…”