Ppg1, a PP2A-Type Protein Phosphatase, Controls Filament Extension and Virulence in Candida albicans

Abstract

b Candida albicans, a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1, encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1, a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1⌬/⌬ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.

Tpd3‐Pph21 phosphatase plays a direct role in Sep7 dephosphorylation in Candida albicans

“…C. albicans contains multiple catalytic subunits of the PP2A family including Pph3, Sit4, Ppg1 and Pph21. Previous studies did not report cell division defects in pph3Δ/Δ , sit4Δ/Δ and ppg1Δ/Δ mutants (Lee et al ., ; Sun et al ., ; Albataineh et al ., ), and we had also confirmed the observations using mutants constructed in our own laboratories (data not shown). A previous study (Lin and Arndt, ) suggested that Pph21 and Pph22 may be involved in cell separation in S. cerevisiae .…”

A Global Analysis of Kinase Function in Candida albicans Hyphal Morphogenesis Reveals a Role for the Endocytosis Regulator Akl1

“…Since the collection contained only 22% phosphatases (and associated proteins), the phosphatase representation in the hyphal morphogenesis-suppressing genes was significantly higher than expected (binomial probability = 3 × 10 −4 ), consistent with the well-studied role of kinases in the signal transduction pathways leading to hyphal morphogenesis. Specific phosphatases in this set that were previously shown to affect hyphal morphogenesis include PSR1 (Elson et al, 2009 ), PTC1 (Hanaoka et al, 2008 ), SHP1 and GLC7 (Hu et al, 2012 ), PPG1 (Albataineh et al, 2014 ), and PPH3 (Sun et al, 2011 ).…”

Regulatory roles of phosphorylation in model and pathogenic fungi

“…In particular, C. albicans Ppg1 has recently been shown to play a critical role in filamentation and virulence 136 and could serve as a promising drug target. Importantly, the catalytic activity of Ppg1 has specifically been shown to be required for pathogenesis and future studies to screen small molecule libraries for inhibitors of Ppg1 phosphatase activity may hold promise.…”

“… 135 An increasing number of Ser/Thr protein phosphatases have been discovered and characterized in fungi, several of which play important cellular functions including cell cycle regulation, growth, protein synthesis, filamentation and maintenance of cellular integrity. 19 , 135 , 136 Interestingly, biochemical analyses of Ser/Thr protein phosphatases in certain filamentous fungi have provided evidence for functional similarities with those studied in higher eukaryotes. 137 – 139 For example, in the presence of calmodulin, a highly conserved catalytic subunit of a N. crassa calmodulin-dependent protein phosphatase showed equivalent phosphatase activity to that of bovine brain calcineurin.…”

“… 254 A recent study has also demonstrated that both a ppg1 Δ/Δ mutant as well as a mutant specifically defective for Ppg1 phosphatase activity show reduced filament extension and invasion as well as highly attenuated virulence in the mouse systemic model. 136 In addition, C. albicans Ppg1 appears to function via the cAMP/PKA filamentous growth pathway. While the ppg1 Δ/Δ virulence defect is most likely attributed to defects in filamentation and invasion, Ppg1 may control other virulence-related processes which have yet to be elucidated.…”