Protein Phosphatases 2A Affects Drug Resistance of Candida albicans Biofilm Via ATG Protein Phosphorylation Induction

Abstract

Objectives

Candida albicans (C. albicans) biofilms are well-known to be resistantto various antifungal agents. Autophagy is crucial for adapting to changes in nutrition conditions. Protein phosphatase 2A (PP2A) is prominent in regulating physiological processes, possibly related to autophagy-related (ATG) protein phosphorylation. This study hypothesizes that PP2A affects biofilm formation and drug resistance of C. albicans via autophagy induction.

Materials and methods

The expressions of PP2A catalytic subunit coding gene PPH21 were compared. The mutant strain (pph21Δ/Δ) was constructed and the biofilm was treated with autophagy activator (rapamycin, Rap). The biofilm formation, drug susceptibility and oxidative stress levels were examined. The autophagic activity was detected, along with the autophagosomes observed. The therapeutic efficacy of the antifungal agents was estimated on the mice model of C. albicans oral infection.

Results

PPH21 was associated with C. albicans biofilm formation and drug resistance. Autophagy activation by rapamycin can induce increased autophagy levels, while it was hindered in pph21Δ/Δ. Besides, the protein levels of Atg13 and Atg1 were significantly down-regulated in pph21Δ/Δ+Rap (P < .01), along with its decreased regulatory capacity to oxidative stress. Autophagy activation can promote biofilm formation and improve drug resistance, while the absence of PPH21 may prevent the enhancement of drug resistance. Autophagy activation reduced the efficacy of antifungal agents in treating oral C. albicans infection in mice, among which pph21Δ/Δ presented better therapeutic effects.

Conclusion

PP2A is important in the autophagy induction of C. albicans by participating in Atg13 phosphorylation, followed by Atg1 activation, further affecting its biofilm formation and drug resistance.

Clinical relevance

PP2A-induced autophagy may be a potential regulatory mechanism of C. albicans drug resistance. This appears to be a promising therapeutic strategy for managing C. albicans-related infectious diseases.