title: Distinct and redundant roles of protein tyrosine phosphatases Ptp1 and Ptp2 in governing the differentiation and pathogenicity of Cryptococcus neoformans.
abstract: Protein tyrosine phosphatases (PTPs) serve as key negative-feedback regulators of mitogen-activated protein kinase (MAPK) signaling cascades. However, their roles and regulatory mechanisms in human fungal pathogens remain elusive. In this study, we characterized the functions of two PTPs, Ptp1 and Ptp2, in Cryptococcus neoformans, which causes fatal meningoencephalitis. PTP1 and PTP2 were found to be stress-inducible genes, which were controlled by the MAPK Hog1 and the transcription factor Atf1. Ptp2 suppressed the hyperphosphorylation of Hog1 and was involved in mediating vegetative growth, sexual differentiation, stress responses, antifungal drug resistance, and virulence factor regulation through the negative-feedback loop of the HOG pathway. In contrast, Ptp1 was not essential for Hog1 regulation, despite its Hog1-dependent induction. However, in the absence of Ptp2, Ptp1 served as a complementary PTP to control some stress responses. In differentiation, Ptp1 acted as a negative regulator, but in a Hog1- and Cpk1-independent manner. Additionally, Ptp1 and Ptp2 localized to the cytosol but were enriched in the nucleus during the stress response, affecting the transient nuclear localization of Hog1. Finally, Ptp1 and Ptp2 played minor and major roles, respectively, in the virulence of C. neoformans. Taken together, our data suggested that PTPs could be exploited as novel antifungal targets.
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Byun
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Jung
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Joohyeon
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Cheong
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea ysbahn@yonsei.ac.kr.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D005260:Female; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005800:Genes, Fungal; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism; D014774:Virulence / Q000235:genetics*
chemical_list: D005656:Fungal Proteins; D014157:Transcription Factors; D017027:Protein Tyrosine Phosphatases
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