Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

Department of Oral Biology, SUNY at Buffalo Main Street Campus, Buffalo, NY 14214, USA.
Eukaryotic Cell (Impact Factor: 3.18). 11/2007; 6(10):1876-88. DOI: 10.1128/EC.00039-07
Source: PubMed


Histatin 5 (Hst 5) is a salivary cationic peptide that has toxicity for Candida albicans by inducing rapid cellular ion imbalance and cell volume loss. Microarray analyses of peptide-treated cells were used to
evaluate global gene responses elicited by Hst 5. The major transcriptional response of C. albicans to Hst 5 was expression of genes involved in adaptation to osmotic stress, including production of glycerol (RHR2, SKO1, and PDC11) and the general stress response (CTA1 and HSP70). The oxidative-stress genes AHP1, TRX1, and GPX1 were mildly induced by Hst 5. Cell defense against Hst 5 was dependent on the Hog1 mitogen-activated protein kinase (MAPK)
pathway, since C. albicans hog1/hog1 mutants were significantly hypersensitive to Hst 5 but not to Mkc1 MAPK or Cek1 MAPK mutants. Activation of the high-osmolarity
glycerol (HOG) pathway was demonstrated by phosphorylation of Hog1 MAPK as well as by glycerol production following Hst 5
treatment in a dose-dependent manner. C. albicans cells prestressed with sorbitol were less sensitive to subsequent Hst 5 treatment; however, cells treated concurrently with
osmotic stress and Hst 5 were hypersensitive to Hst 5. In contrast, cells subjected to oxidative stress had no difference
in sensitivity to Hst 5. These results suggest a common underlying cellular response to osmotic stress and Hst 5. The HOG
stress response pathway likely represents a significant and effective challenge to physiological levels of Hst 5 and other
toxic peptides in fungal cells.

Download full-text


Available from: Slavena Vylkova, Jan 27, 2015
    • "The killing of C. albicans is accompanied by the release of intracellular potassium ions, and the TRK1 potassium channel is critical (Pollock et al., 1984; Xu et al., 1999; Baev et al., 2004). Histatins inhibit respiration and induce the formation of reactive oxygen species in C. albicans cells (Helmerhorst et al., 2001) and induce an osmotic stress response (Vylkova et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although innate immunity came into the research spotlight in the late 1990s when its instructive role in the adaptive immune response was recognized, innate humoral defense factors have a much older history. The exocrine secretions of the body contain a plethora of distinct soluble factors (lysozyme, lactoferrin, peroxidases, proline-rich proteins, histatins, etc.) that protect the body from mucosal microbial pathogens. More recent studies have established that the humoral arm of innate immunity contains a heterogeneous group of pattern-recognition molecules (e.g., pentraxins, collectins, and ficolins), which perform diverse host-defense functions, such as agglutination and neutralization, opsonization, control of inflammation, and complement activation and regulation. These pattern-recognition molecules, which act as functional predecessors of antibodies ("ante-antibodies"), and the classic soluble innate defense factors form an integrated system with complementary specificity, action, and tissue distribution, and they are the subject of this chapter.
    No preview · Article · Dec 2015
  • Source
    • "Further studies are necessary to clarify the roles of Bcr1 and Ssd1 in early versus late mechanisms of resistance to AMPs. The Hog1 (high osmolarity glycerol) MAPK pathway, which provides a response to osmotic, oxidative, and heavy-metal exposure stresses in fungal cells, was shown to be activated in the presence of AMPs, such as NaD1, HBD2, HBD3, and histatin-5 (a salivary cationic AMP that has a role in keeping C. albicans in its commensal state; Yeaman et al., 1996; Vylkova et al., 2007; Argimon et al., 2011; Hayes et al., 2013). The injuries imposed on C. albicans by these defensins seem to share common features with osmotic and/or oxidative stress (Argimon et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed.
    Full-text · Article · Mar 2014 · Frontiers in Microbiology
  • Source
    • "J Biol Chem 285(48):37513–37520 87. Lobo DS et al (2007) Antifungal Pisum sativum defensin 1 interacts with Neurospora crassa cyclin F related to the cell cycle. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Antimicrobial peptides are a vital component of the innate immune system of all eukaryotic organisms and many of these peptides have potent antifungal activity. They have potential application in the control of fungal pathogens that are a serious threat to both human health and food security. Development of antifungal peptides as therapeutics requires an understanding of their mechanism of action on fungal cells. To date, most research on antimicrobial peptides has focused on their activity against bacteria. Several antimicrobial peptides specifically target fungal cells and are not active against bacteria. Others with broader specificity often have different mechanisms of action against bacteria and fungi. This review focuses on the mechanism of action of naturally occurring antifungal peptides from a diverse range of sources including plants, mammals, amphibians, insects, crabs, spiders, and fungi. While antimicrobial peptides were originally proposed to act via membrane permeabilization, the mechanism of antifungal activity for these peptides is generally more complex and often involves entry of the peptide into the cell.
    Full-text · Article · Feb 2013 · Cellular and Molecular Life Sciences CMLS
Show more