PP2A-Like Protein Phosphatase (Sit4) Regulatory Subunits, Sap155 and Sap190, Regulate Candida albicans' Cell Growth, Morphogenesis, and Virulence.

Qi Han,Jianli Sang,Linpeng Zhao,Yue Wang,Yueqing Wang,Chaoying Pan

doi:10.3389/fmicb.2019.02943

Abstract

PP2A-like phosphatases share high homology with PP2A enzymes and are composed of a catalytic subunit and a regulatory subunit. In Candida albicans, the PP2A-like catalytic subunit SIT4 regulates cell growth, morphogenesis, and virulence. However, the functions of its regulatory subunits remain unclear. Here, by homology analysis and co-IP experiments, we identified two regulatory subunits of SIT4 in C. albicans, SAP155 (orf19.642) and SAP190 (orf19.5160). We constructed sit4Δ/Δ, sap155Δ/Δ, sap190Δ/Δ, and sap155Δ/Δ sap190Δ/Δ mutants and found that deleting SAP155 had no apparent phenotypic consequence, while deleting SAP190 caused slow growth, hypersensitivity to cell wall stress, abnormal morphogenesis in response to serum or genotoxic stress (HU and MMS), less damage to macrophages, and attenuated virulence in mice. However, deleting both SAP155 and SAP190 caused significantly stronger defects, which was similar to deleting SIT4. Together, our results suggest that SAP190 is required for the function of SIT4 and that SAP155 can partially compensate for the loss of SAP190 in C. albicans. Given the vital role of these regulatory subunits of SIT4 in C. albicans physiology and virulence, they could serve as potential antifungal targets.

Highlights

Candida albicans (Ca) is a commensal organism of the oral cavity, gastrointestinal tract, and vagina (Arendrup, 2013; Hebecker et al, 2014)
In the C. albicans genome database, orf19.642 and orf19.5160 are designated as the regulatory subunits of Sit4, and their aminoacid sequence homologies with ScSap4/cSap155/ScSap185/ ScSap190 are 23.3%/26.5%/23.8%/24.9% and 26.2%/26.5%/ 30.9%/35.0%, respectively (Supplementary Figure S1)
To further investigate whether Sap155 and Sap190 are regulatory subunits of Sit4 in C. albicans, we tested whether Sap155 and Sap190 physically interact with Sit4

Summary

Introduction

Candida albicans (Ca) is a commensal organism of the oral cavity, gastrointestinal tract, and vagina (Arendrup, 2013; Hebecker et al, 2014). When the host immune system is compromised, such as under conditions of long-term antibiotic treatment, immunodeficiency, or chemotherapy, C. albicans can cause mucocutaneous and life-threatening disseminated infections (Romani, 2011; Goulart et al, 2018). C. albicans is the fourth most common cause of hospital-acquired systemic infections with a crude mortality rate of more than 50% in the United States (Lai et al, 2008; Pfaller and Diekema, 2010). C. albicans can grow as several cell types, including yeast, pseudohyphae, and true hyphae (Sudbery et al, 2004). Yeast form helps its spread, while hyphae have strong ability of tissue adhesion and invasion (Berman and Sudbery, 2002; Zhu and Filler, 2010).

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