PAR2-β-arrestin 2-ERK axis mediates Malassezia globosa-induced IL-17 response by disrupting ZO-1 in keratinocytes

Malassezia, a lipid-dependent commensal yeast of human skin, also functions as an opportunistic pathogen contributed to the pathogenesis of various skin and systemic diseases. Although the association between Protease-activated Receptor 2 (PAR2) and Fungal infections has been partially characterized, its specific role in Malassezia-related dermatoses remains poorly elucidated. In this study, we demonstrated that PAR2 interacted with Zonula occludens-1 (ZO-1) and β-arrestin 2 to cooperatively regulate M. globosa-infected keratinocytes by Co-IP, PLA, and MbYTH. Utilizing Malassezia folliculitis patient samples, cellular Infection models, and murine Infection models, we demonstrated that M. globosa exploited the PAR2-β-arrestin 2-ERK signaling axis by disrupting ZO-1, consequently amplifying IL-17-mediated inflammatory responses. Notably, pharmacological inhibition or genetic ablation of PAR2 attenuated the Malassezia-induced IL-17 inflammation. Collectively, our results clarify PAR2 as a potential therapeutic target for Malassezia-infected diseases, while providing new insights into the pathogenic mechanisms of commensal fungi.