The RAM Network in Pathogenic Fungi

Abstract

The regulation of Ace2 and morphogenesis (RAM) network is a protein kinase signaling pathway conserved among eukaryotes from yeasts to humans. Among fungi, the RAM network has been most extensively studied in the model yeast Saccharomyces cerevisiae and has been shown to regulate a range of cellular processes, including daughter cell-specific gene expression, cell cycle regulation, cell separation, mating, polarized growth, maintenance of cell wall integrity, and stress signaling. Increasing numbers of recent studies on the role of the RAM network in pathogenic fungal species have revealed that this network also plays an important role in the biology and pathogenesis of these organisms. In addition to providing a brief overview of the RAM network in S. cerevisiae, we summarize recent developments in the understanding of RAM network function in the human fungal pathogens Candida albicans, Candida glabrata, Cryptococcus neoformans, Aspergillus fumigatus, and Pneumocystis spp. Awide variety of key physiological processes in eukaryotic cells are regulated by networks of protein kinase-based signaling pathways. Accordingly, the study of these pathways has been the focus of intense research efforts in nearly every area of eukaryotic cell biology. Because a large number of protein kinase signaling pathways and cascades are highly conserved between model organisms and humans, our current understanding of many mechanistic paradigms for protein kinase-based cell signaling has developed from studies of model organisms, such as the budding yeast Saccharomyces cerevisiae (10). These studies not only have contributed to our fundamental understanding of eukaryotic biology but also have had profound biomedical implications (28). For example, protein kinases are frequently dysregulated in cancer cells, and consequently, protein kinase inhibitors such as imatinib have emerged as important components of current anticancer therapies (19).A second area of eukaryotic biology with important biomedical relevance that has benefited from S. cerevisiae-based studies of protein kinase signaling pathways is the study of pathogenic fungi (26,45). The ability of modern medicine to support patients with compromised immune function and the development of immunomodulatory therapies have contributed to an increase in the morbidity and mortality attributable to invasive fungal infections (14). As the medical importance of pathogenic fungi has increased, so too has interest in the fundamental biology of these organisms as well as the mechanistic basis of their pathogenesis (68). As a result, the study of protein kinase signaling networks has led to many important insights into fungal virulence, host-pathogen interactions, and, more recently, new approaches to antifungal therapy (1).An excellent example of a signaling pathway that is highly conserved within all eukaryotes, is well-studied in S. cerevisiae, and is currently being characterized in pathogenic fungi is the regulation of Ace2 and morphogenesis (RAM) network (65). In this minireview, we s...

Efg1 Directly RegulatesACE2Expression To Mediate Cross Talk between the cAMP/PKA and RAM Pathways during Candida albicans Morphogenesis

“…The RAM signaling pathway regulates a variety of cellular processes in both model and pathogenic fungi (4,45). The best-characterized functions of the RAM pathway are those associated with the transcription factor Ace2.…”

“…Because Ace2 is well known to play an important role in daughter cell transcriptional regulation (17,18,45), we were interested in whether the loss of Ace2 function would have an effect on the emergence of yeast from hyphae. Interestingly, the number of emerging yeast from ace2⌬/⌬ hyphae does not appear to differ from that of the wild type, indicating that Ace2 is not required for the budding process (Fig.…”

Surface Stress Induces a Conserved Cell Wall Stress Response in the Pathogenic Fungus Candida albicans

“…5). The protein kinase Cbk1 and the transcription factor Ace2, which participate in the RAM (regulation of Ace2 and morphogenesis) pathway (54), are major regulators of wall and secreted proteins. The expression levels of both CHT3 and ENG1 decrease about 3-fold when ACE2 is knocked out (55).…”

Complex Haploinsufficiency-Based Genetic Analysis of the NDR/Lats Kinase Cbk1 Provides Insight into Its Multiple Functions in Candida albicans

“…Although it has been clearly linked to cell cycle and to daughter cell-specific gene expression (Saputo et al 2012;Weiss 2012), little is known regarding the potential function of the RAM pathway within other pathways that regulate cell morphogenesis and polarity. Our screens identified two genes that interact with CBK1 and are related, or are potentially related, to Cdc42 function.…”

“…The RAM pathway is centered on the Ndr/Lats family protein kinase Cbk1 (FungiDB: orf19.4909 ) and its transcription factor substrate Ace2 (FungiDB: orf19.6124 ). In addition to these two effector proteins, the RAM network includes Mob2, a Cbk1-binding protein required for kinase activity; Kic1, a kinase of unclear function; and the accessory proteins Tao3, Hym1, and Sog2 (Saputo et al 2012). Recent work has shown that Cbk1 also phosphorylates Bcr1 (FungiDB: orf19.723 ), a transcription factor involved in biofilm formation (Gutierrez-Escribino et al 2012), and the Fkh2, a forkhead transcription factor (Grieg et al 2015), involved in morphogenesis.…”