Aspartyl protease MfSAP2 is a key virulence factor in mycelial form of skin fungi <i>Malassezia furfur</i>

Malassezia is the dominant genus of fungi residing on human skin and is associated with both healthy skin and many dermatological conditions. Among these skin diseases, pityriasis versicolor (PV) has strong etiological connections with Malassezia. In the hyper- or hypo-pigmented scales of PV patients, Malassezia is enriched in its mycelial form, which is rarely present on healthy skin. How these Malassezia hyphae contribute to disease pathology in PV is unknown. In this study, we observed a distinct shift in the extracellular proteolytic activity when Malassezia furfur transitions from yeast to hyphae. We identified that the expression of the aspartyl protease MfSAP2 is dramatically up-regulated at both the mRNA and protein level when M. furfur is in the mycelial form. We determined the protease substrate specificity and observed that MfSAP2 can degrade corneodesmosome proteins, which are intercellular adhesive proteins between corneocytes in the stratum corneum. In a 3D human skin model with MfSAP2 treatment, we observed clear degradation of corneodesmosin, a component of the corneodesmosome. Taken together, our study demonstrates that a secreted protease is a key virulence factor associated with M. furfur mycelium and is potentially involved in the disease pathogenesis of PV.