Ras Signaling Gets Fine-Tuned: Regulation of Multiple Pathogenic Traits of Candida albicans

Abstract

a Candida albicans is an opportunistic fungal pathogen that can cause disseminated infection in patients with indwelling catheters or other implanted medical devices. A common resident of the human microbiome, C. albicans responds to environmental signals, such as cell contact with catheter materials and exposure to serum or CO 2 , by triggering the expression of a variety of traits, some of which are known to contribute to its pathogenic lifestyle. Such traits include adhesion, biofilm formation, filamentation, white-to-opaque (W-O) switching, and two recently described phenotypes, finger and tentacle formation. Under distinct sets of environmental conditions and in specific cell types (mating type-like a [MTLa]/alpha cells, MTL homozygotes, or daughter cells), C. albicans utilizes (or reutilizes) a single signal transduction pathway-the Ras pathway-to affect these phenotypes. Ras1, Cyr1, Tpk2, and Pde2, the proteins of the Ras signaling pathway, are the only nontranscriptional regulatory proteins that are known to be essential for regulating all of these processes. How does C. albicans utilize this one pathway to regulate all of these phenotypes? The regulation of distinct and yet related processes by a single, evolutionarily conserved pathway is accomplished through the use of downstream transcription factors that are active under specific environmental conditions and in different cell types. In this minireview, we discuss the role of Ras signaling pathway components and Ras pathway-regulated transcription factors as well as the transcriptional regulatory networks that fine-tune gene expression in diverse biological contexts to generate specific phenotypes that impact the virulence of C. albicans.

Analysis of the Candida albicans Phosphoproteome

“…Ras1 interacts activates adenylate cyclase Cyr1 (73), and the resulting increase in cAMP activates the catalytic subunits of protein kinase A (Tpk1 and -2) by causing their release from the regulatory subunit Bcy1. The activated PKA subunits likely have many targets, such as transcription factors, including Efg1 (72,74). In S. cerevisiae, Bcy1 itself is regulated by phosphorylation, in part by PKA subunits.…”

Candida Survival Strategies

“…Consequently, most pathways do not regulate filamentation discretely but are part of a complex regulatory network that is yet not fully understood. More detailed information on the involved pathways can be found in several recent reviews Hogan & Muhlschlegel, 2011;Huang, 2012;Inglis & Sherlock, 2013;Shapiro et al, 2011;Sudbery, 2011). Finally, the different signaling pathways lead to activation or inhibition of key transcriptional regulators, e.g., Efg1, Czf1, Cph1, Tec1, Flo8, and Nrg1, that control expression of genes necessary for hypha formation and hypha-associated genes (Brown, Giusani, Chen, & Kumamoto, 1999;Cao, Lane, Raniga, Lu, Zhou, Ramon, et al, 2006;Giusani, Vinces, & Kumamoto, 2002;Huang, 2012;Kumamoto & Vinces, 2005b;Leberer, Harcus, Broadbent, Clark, Dignard, Ziegelbauer, et al, 1996;Liu, Kohler, & Fink, 1994;Murad et al, 2001;Schweizer, Rupp, Taylor, Rollinghoff, & Schroppel, 2000;Shapiro et al, 2011;Stoldt et al, 1997;Vinces, Haas, & Kumamoto, 2006).…”

“…Nrg1, Tup1, and Rfg1, as well as the stress-activated Hog1 pathway are important negative regulators of morphogenesis (Inglis & Sherlock, 2013;Shapiro et al, 2011;Sudbery, 2011). Especially Ras1 and Cyr1 play a crucial role since they integrate a wide range of environmental signals, and in case of Ras1 may even activate a variety of cell signaling cascades (Hogan & Muhlschlegel, 2011;Inglis & Sherlock, 2013). This leads to simultaneous integration of diverse signals to regulate morphogenesis, and allows the coregulation of morphogenesis with a wide variety of other fitness/virulence attributes.…”

“…Indeed, hypha formation is triggered by environmental signals that resemble unfavorable growth conditions or indicate a putatively hostile environment. Such factors include the presence of serum, elevated temperature, neutral pH, presence of certain nutrients, starvation signals, matrix embedding, CO 2 and O 2 levels, cell density, and contact to physical surfaces (Inglis & Sherlock, 2013;Sudbery, 2011). It is intriguing how many of these factors resemble growth conditions the fungus might encounter in the human host (Cottier & Muhlschlegel, 2009;Sudbery, 2011).…”

“…These pathways include the inhibition of heat shock protein 90 (Hsp90) by elevated temperatures and subsequent activation of Ras1, the cAMP/PKA-signaling pathway via direct or indirect activation of the adenylyl cyclase Cyr1, mitogen activated protein kinase (MAPK) signaling via Ras1/Hst7 and Cek1, activation of the Rim101 pathway by neutral to alkaline pH, Czf1 activation under embedded conditions via Rac1, hypoxia-induced Efg1/Efh1 activation, and reactive oxygen species (ROS) signaling induced by genotoxic stress (Gow, van de Veerdonk, Brown, & Netea, 2012;Huang, 2012;Inglis & Sherlock, 2013;Shapiro, Robbins, & Cowen, 2011;Sudbery, 2011). Nrg1, Tup1, and Rfg1, as well as the stress-activated Hog1 pathway are important negative regulators of morphogenesis (Inglis & Sherlock, 2013;Shapiro et al, 2011;Sudbery, 2011). Especially Ras1 and Cyr1 play a crucial role since they integrate a wide range of environmental signals, and in case of Ras1 may even activate a variety of cell signaling cascades (Hogan & Muhlschlegel, 2011;Inglis & Sherlock, 2013).…”