A Malassezia pseudoprotease dominates the secreted hydrolase landscape and is a potential allergen on skin

A Malassezia pseudoprotease dominates the secreted hydrolase landscape and is a potential allergen on skin

Biochimie

10.1016/j.biochi.2023.09.023

http://dx.doi.org/10.1016/j.biochi.2023.09.023

Wisely Chua, Carl O. Marsh, Si En Poh, Winston LC. Koh, Melody Li Ying Lee, Li Fang Koh, Xin-Zi Emily Tang, Peter See, Zheng Ser, Shi Mei Wang, Radoslaw M. Sobota, Thomas L. Dawson, Yik Weng Yew, Steven Thng, Anthony J. O’Donoghue, Hazel H. Oon, John E. Common, Hao Li

24 September 2023

Chua, W., Marsh, C. O., Poh, S. E., Koh, W. LC., Lee, M. L. Y., Koh, L. F., Tang, X.-Z. E., See, P., Ser, Z., Wang, S. M., Sobota, R. M., Dawson, T. L., Yew, Y. W., Thng, S., O’Donoghue, A. J., Oon, H. H., Common, J. E., & Li, H. (2024). A Malassezia pseudoprotease dominates the secreted hydrolase landscape and is a potential allergen on skin. Biochimie, 216, 181–193. https://doi.org/10.1016/j.biochi.2023.09.023

Malassezia globosa is abundant and prevalent on sebaceous areas of the human skin. Genome annotation reveals that M. globosa possesses a repertoire of secreted hydrolytic enzymes relevant for lipid and protein metabolism. However, the functional significance of these enzymes is uncertain and presence of these genes in the genome does not always translate to expression at the cutaneous surface. In this study we utilized targeted RNA sequencing from samples isolated directly from the skin to quantify gene expression of M. globosa secreted proteases, lipases, phospholipases and sphingomyelinases. Our findings indicate that the expression of these enzymes is dynamically regulated by the environment in which the fungus resides, as different growth phases of the planktonic culture of M. globosa show distinct expression levels. Furthermore, we observed significant differences in the expression of these enzymes in culture compared to healthy sebaceous skin sites. By examining the in situ gene expression of M. globosa's secreted hydrolases, we identified a predicted aspartyl protease, MGL_3331, which is highly expressed on both healthy and disease-affected dermatological sites. However, molecular modeling and biochemical studies revealed that this protein has a non-canonical active site motif and lacks measurable proteolytic activity. This pseudoprotease MGL_3331 elicits a heightened IgE-reactivity in blood plasma isolated from patients with atopic dermatitis compared to healthy individuals and invokes a pro-inflammatory response in peripheral blood mononuclear cells. Overall, our study highlights the importance of studying fungal proteins expressed in physiologically relevant environments and underscores the notion that secreted inactive enzymes may have important functions in influencing host immunity.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the A*STAR-NRF-EDB - IAF-PP - Asian Skin Microbiome Program
Grant Reference no. : H18/01/a0/016

This research / project is supported by the A*STAR-NRF-EDB - IAF-PP - Asian Skin Microbiome Program 2.0
Grant Reference no. : H22/J1/a0/040

This research / project is supported by the Ministry of Education - AcRF Tier 1 grant
Grant Reference no. : R143-000-B79-114

This research / project is supported by the Ministry of Education - AcRF Tier 1 grant
Grant Reference no. : R-143-000-C16-114

This research is supported by core funding from: A*STAR BMRC
Grant Reference no. : ATR

This research / project is supported by the A*STAR-NRF-EDB - IAF-PP - Skin Research Institute of Singapore
Grant Reference no. : H17/01/a0/004

This research / project is supported by the Singapore Ministry of Health’s / National Medical Research Council - Open Fund-Individual Research Grant (OFIRG)
Grant Reference no. : MOH-000612-00

This research / project is supported by the A*STAR - Central Research Fund
Grant Reference no. : NA

This research / project is supported by the A*STAR - Young Achiever’s Award
Grant Reference no. : NA

This research / project is supported by the A*STAR - Career Development award
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/20604

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