Sho1 and Msb2 Play Complementary but Distinct Roles in Stress Responses, Sexual Differentiation, and Pathogenicity of Cryptococcus neoformans

Abstract

The high-osmolarity glycerol response (HOG) pathway is pivotal in environmental stress response, differentiation, and virulence of Cryptococcus neoformans, which causes fatal meningoencephalitis. A putative membrane sensor protein, Sho1, has been postulated to regulate HOG pathway, but its regulatory mechanism remains elusive. In this study, we characterized the function of Sho1 with relation to the HOG pathway in C. neoformans. Sho1 played minor roles in osmoresistance, thermotolerance, and maintenance of membrane integrity mainly in a HOG-independent manner. However, it was dispensable for cryostress resistance, primarily mediated through the HOG pathway. A mucin-like transmembrane (TM) protein, Msb2, which interacts with Sho1 in Saccharomyces cerevisiae, was identified in C. neoformans, but found not to interact with Sho1. MSB2 codeletion with SHO1 further decreased osmoresistance and membrane integrity, but not thermotolerance, of sho1Δ mutant, indicating that both factors play to some level redundant but also discrete roles in C. neoformans. Sho1 and Msb2 played redundant roles in promoting the filamentous growth in sexual differentiation in a Cpk1-independent manner, in contrast to the inhibitory effect of the HOG pathway in the process. However, both factors contributed independently to Cpk1 phosphorylation during vegetative growth and endoplasmic reticulum (ER) stress response. Finally, Sho1 and Msb2 play distinct but complementary roles in the pulmonary virulence of C. neoformans. Overall, Sho1 and Msb2 play complementary but distinct roles in stress response, differentiation, and pathogenicity of C. neoformans.

The Verticillium dahliae Sho1‐MAPK pathway regulates melanin biosynthesis and is required for cotton infection

“…Many recent studies of Sho1 orthologs in fungi have demonstrated that Sho1 plays a critical role in pathogenesis, and this role may overlap with the signal transducing roles of other surface sensors (Msb2, Sln1, etc.) (Lanver et al, 2010;Zhang et al, 2010;Liu et al, 2011;Gu et al, 2015;Perez-Nadales and Di Pietro, 2015;So et al, 2018;Ren et al, 2019). For instance, FgSho1 and FgSln1 have an additive effect on the pathogenicity of F. graminearum on wheat (Gu et al, 2015).…”

Stress-Activated Protein Kinases in Human Fungal Pathogens

“…The interesting exception to this is responses to osmotic stress, as osmotic stress-induced dephosphorylation of Hog1 and resistance to this stress are Ssk1-independent (Bahn et al, 2006). This suggests the existence of an additional two-component independent pathway that relays osmotic stress signals to Hog1 but, in contrast to S. cerevisiae , this is not governed by the Sho1/Msb2 pathway (So et al, 2018). As in S. cerevisiae , deletion of the Ypd1 phosphorelay protein gives a lethal phenotype in C. neoformans and this is dependent on Hog1 presence (Lee et al, 2011).…”

Putative Membrane Receptors Contribute to Activation and Efficient Signaling of Mitogen-Activated Protein Kinase Cascades during Adaptation of Aspergillus fumigatus to Different Stressors and Carbon Sources

“… C. albicans Msb2p is a global regulator of temperature stress ( 46 ), while OPY2 mutants display susceptibility to CR, but it did not play a role in the adaptation to high osmolarity or oxidative stress and virulence in the Galleria mellonella model ( 47 ). Sho1 and Msb2 homologues play complementary but distinct roles in stress responses, differentiation, and pathogenicity of the human pathogen Cryptococcus neoformans ( 48 ). In the dimorphic plant-pathogenic fungus Ustilago maydis , Sho1 and Msb2-like proteins play a key role during appressorium differentiation and are involved in plant surface sensing ( 49 ).…”