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Oxidative stress responses in the human fungal pathogen, Candida albicans.

Dantas Ada S, Day A, Ikeh M, Kos I, Achan B, Quinn J - Biomolecules (2015)

Bottom Line: Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years.Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference.In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Biologia Celular e Genética, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro 20550-013, Brazil. alesdantas@gmail.com.

ABSTRACT
Candida albicans is a major fungal pathogen of humans, causing approximately 400,000 life-threatening systemic infections world-wide each year in severely immunocompromised patients. An important fungicidal mechanism employed by innate immune cells involves the generation of toxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. Consequently, there is much interest in the strategies employed by C. albicans to evade the oxidative killing by macrophages and neutrophils. Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years. Key findings include the observations that hydrogen peroxide triggers the filamentation of this polymorphic fungus and that a superoxide dismutase enzyme with a novel mode of action is expressed at the cell surface of C. albicans. Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference. In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen.

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H2O2-induced activation of Cap1 is inhibited in the presence of cations. (A) Exposure of C. albicans to H2O2 promotes the Gpx3/Ybp1-mediated oxidation and activation the Cap1 transcription factor (Cap1ox). Cap1ox can no longer interact with the Crm1 nuclear export factor resulting in its nuclear accumulation, and the subsequent Cap1-dependent induction of genes with antioxidant functions necessary for cell survival. Following cellular adaptation, Cap1ox is returned to the inactive reduced form (Cap1RED) by thioredoxin (Trx1); (B) Remarkably, when C. albicans cells are exposed to H2O2 in the presence of cations, Cap1 fails to accumulate in the nucleus and therefore antioxidant gene expression is not induced leading to cell death. This is important as, following phagocytosis, C. albicans is exposed simultaneously to ROS and cationic fluxes. See text for details.
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biomolecules-05-00142-f001: H2O2-induced activation of Cap1 is inhibited in the presence of cations. (A) Exposure of C. albicans to H2O2 promotes the Gpx3/Ybp1-mediated oxidation and activation the Cap1 transcription factor (Cap1ox). Cap1ox can no longer interact with the Crm1 nuclear export factor resulting in its nuclear accumulation, and the subsequent Cap1-dependent induction of genes with antioxidant functions necessary for cell survival. Following cellular adaptation, Cap1ox is returned to the inactive reduced form (Cap1RED) by thioredoxin (Trx1); (B) Remarkably, when C. albicans cells are exposed to H2O2 in the presence of cations, Cap1 fails to accumulate in the nucleus and therefore antioxidant gene expression is not induced leading to cell death. This is important as, following phagocytosis, C. albicans is exposed simultaneously to ROS and cationic fluxes. See text for details.

Mentions: Similar to that reported for S. cerevisiae Yap1, C. albicans Cap1 rapidly accumulates in the nucleus in response to H2O2 [56,67]. Under non-stressed conditions, Yap1 shuttles between the cytoplasm and the nucleus due to the interaction of a nuclear export sequence (NES), located at the C-terminus of these transcription factors, with the Crm1 nuclear export factor [71]. However, following exposure to H2O2, Yap1 is activated by oxidation of specific cysteine residues, resulting in disulphide bond formation between two cysteine-rich domains (n-CRD and c-CRD). This triggers a conformational change within Yap1 that masks the NES, thereby preventing its interaction with Crm1. The inability to be recognized by Crm1 leads to the nuclear accumulation of Yap1, the nuclear-dependent phosphorylation of this transcription factor and the induction of Yap1-dependent genes [72]. Conversely, activation of Yap1 is counteracted by the thioredoxins Trx1 and Trx2, which function to reduce oxidised Yap1 [72]. This basic mechanism of regulation is conserved in C. albicans (Figure 1). Mutation of the c-CRD affects Cap1 regulation [67], and Cap1 is rapidly oxidised following exposure to H2O2 [42]. In addition, following the nuclear accumulation of Cap1, this transcription factor becomes phosphorylated, and the induction of Cap1-dependent genes is observed. Furthermore, as seen in S. cerevisiae, thioredoxin functions to reverse the H2O2-induced oxidation and activation of Cap1 [42].


Oxidative stress responses in the human fungal pathogen, Candida albicans.

Dantas Ada S, Day A, Ikeh M, Kos I, Achan B, Quinn J - Biomolecules (2015)

H2O2-induced activation of Cap1 is inhibited in the presence of cations. (A) Exposure of C. albicans to H2O2 promotes the Gpx3/Ybp1-mediated oxidation and activation the Cap1 transcription factor (Cap1ox). Cap1ox can no longer interact with the Crm1 nuclear export factor resulting in its nuclear accumulation, and the subsequent Cap1-dependent induction of genes with antioxidant functions necessary for cell survival. Following cellular adaptation, Cap1ox is returned to the inactive reduced form (Cap1RED) by thioredoxin (Trx1); (B) Remarkably, when C. albicans cells are exposed to H2O2 in the presence of cations, Cap1 fails to accumulate in the nucleus and therefore antioxidant gene expression is not induced leading to cell death. This is important as, following phagocytosis, C. albicans is exposed simultaneously to ROS and cationic fluxes. See text for details.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384116&req=5

biomolecules-05-00142-f001: H2O2-induced activation of Cap1 is inhibited in the presence of cations. (A) Exposure of C. albicans to H2O2 promotes the Gpx3/Ybp1-mediated oxidation and activation the Cap1 transcription factor (Cap1ox). Cap1ox can no longer interact with the Crm1 nuclear export factor resulting in its nuclear accumulation, and the subsequent Cap1-dependent induction of genes with antioxidant functions necessary for cell survival. Following cellular adaptation, Cap1ox is returned to the inactive reduced form (Cap1RED) by thioredoxin (Trx1); (B) Remarkably, when C. albicans cells are exposed to H2O2 in the presence of cations, Cap1 fails to accumulate in the nucleus and therefore antioxidant gene expression is not induced leading to cell death. This is important as, following phagocytosis, C. albicans is exposed simultaneously to ROS and cationic fluxes. See text for details.
Mentions: Similar to that reported for S. cerevisiae Yap1, C. albicans Cap1 rapidly accumulates in the nucleus in response to H2O2 [56,67]. Under non-stressed conditions, Yap1 shuttles between the cytoplasm and the nucleus due to the interaction of a nuclear export sequence (NES), located at the C-terminus of these transcription factors, with the Crm1 nuclear export factor [71]. However, following exposure to H2O2, Yap1 is activated by oxidation of specific cysteine residues, resulting in disulphide bond formation between two cysteine-rich domains (n-CRD and c-CRD). This triggers a conformational change within Yap1 that masks the NES, thereby preventing its interaction with Crm1. The inability to be recognized by Crm1 leads to the nuclear accumulation of Yap1, the nuclear-dependent phosphorylation of this transcription factor and the induction of Yap1-dependent genes [72]. Conversely, activation of Yap1 is counteracted by the thioredoxins Trx1 and Trx2, which function to reduce oxidised Yap1 [72]. This basic mechanism of regulation is conserved in C. albicans (Figure 1). Mutation of the c-CRD affects Cap1 regulation [67], and Cap1 is rapidly oxidised following exposure to H2O2 [42]. In addition, following the nuclear accumulation of Cap1, this transcription factor becomes phosphorylated, and the induction of Cap1-dependent genes is observed. Furthermore, as seen in S. cerevisiae, thioredoxin functions to reverse the H2O2-induced oxidation and activation of Cap1 [42].

Bottom Line: Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years.Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference.In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Biologia Celular e Genética, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro 20550-013, Brazil. alesdantas@gmail.com.

ABSTRACT
Candida albicans is a major fungal pathogen of humans, causing approximately 400,000 life-threatening systemic infections world-wide each year in severely immunocompromised patients. An important fungicidal mechanism employed by innate immune cells involves the generation of toxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. Consequently, there is much interest in the strategies employed by C. albicans to evade the oxidative killing by macrophages and neutrophils. Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years. Key findings include the observations that hydrogen peroxide triggers the filamentation of this polymorphic fungus and that a superoxide dismutase enzyme with a novel mode of action is expressed at the cell surface of C. albicans. Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference. In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen.

Show MeSH
Related in: MedlinePlus