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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 the Hog1 SAPK. In response to H2O2, Hog1 becomes rapidly phosphorylated and accumulates in the nucleus, and C. albicans cells lacking Hog1 are sensitive to oxidative stress. Proteins required for H2O2-induced activation of Hog1 are shown in green. These include the response regulator Ssk1 (but no other two-component protein), the redox sensitive antioxidants Tsa1 and Trx1, and the mitochondria biogenesis factor Fzo1. Following H2O2-induced activation, Hog1 phosphorylates the Mkc1 MAPK. However, cells lacking Mkc1 are not sensitive to oxidative stress, suggesting that an, as yet, unknown Hog1 substrate(s), mediates oxidative stress resistance.
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biomolecules-05-00142-f002: H2O2-induced activation of the Hog1 SAPK. In response to H2O2, Hog1 becomes rapidly phosphorylated and accumulates in the nucleus, and C. albicans cells lacking Hog1 are sensitive to oxidative stress. Proteins required for H2O2-induced activation of Hog1 are shown in green. These include the response regulator Ssk1 (but no other two-component protein), the redox sensitive antioxidants Tsa1 and Trx1, and the mitochondria biogenesis factor Fzo1. Following H2O2-induced activation, Hog1 phosphorylates the Mkc1 MAPK. However, cells lacking Mkc1 are not sensitive to oxidative stress, suggesting that an, as yet, unknown Hog1 substrate(s), mediates oxidative stress resistance.

Mentions: Stress-activated MAPKs are conserved signalling molecules that promote the ability of cells to adapt to environmental change [82]. They are components of a three-tiered core signalling module that comprises the SAPK itself, a MAP kinase kinase (MAPKK) and a MAPKK kinase (MAPKKK). Activation of the MAPKKK results in the phosphorylation and activation of the MAPKK, which, in turn, culminates in the phosphorylation of the SAPK on conserved threonine and tyrosine residues located within the TGY motif in the phosphorylation lip of the catalytic domain. This induces the activation and nuclear accumulation of the kinase [83] and the proline-directed phosphorylation of Ser/Thr residues on diverse substrates, including transcription factors, kinases, cell cycle regulators and membrane proteins, thus eliciting appropriate cellular responses. In C. albicans, Hog1 is robustly phosphorylated and rapidly accumulates in the nucleus following exposure of cells to H2O2 [33]. In addition, cells lacking Hog1 display increased sensitivity to a range of ROS, indicating that Hog1 activation is a critical component of the oxidative stress response in C. albicans [84,85]. Interestingly, Hog1 is only activated following exposure of C. albicans cells to relatively high levels of H2O2 compared to the analogous Sty1 SAPK in the model yeast, S. pombe. This may reflect an adaption of this pathogenic fungus to restrict Hog1 activation to ROS-rich environments during infection [85]. Despite the increased H2O2 sensitivity exhibited by hog1Δ cells and significant phosphorylation of Hog1 in response to H2O2, transcript profiling experiments revealed that Hog1 is largely dispensable for H2O2-induced gene expression [33]. Although a small subset of H2O2-responsive genes were identified that showed Hog1-dependent induction, subsequent analysis failed to identify any genes coding for proteins with known antioxidant functions [33]. This is in contrast with S. pombe, where Sty1 is required for the activation of the core stress genes in response to H2O2, including genes encoding important antioxidants, such as catalase and glutathione peroxidase [86]. What, therefore, is the role of Hog1 in the C. albicans oxidative stress response if it is not required for the induction of antioxidant gene expression? One possibility is that Hog1 contributes to the oxidative stress response at a post-transcriptional level in C. albicans. Indeed, the S. pombe Sty1 SAPK has been shown to interact with translation factors [87]. However, Hog1 does not play a major role in regulating the oxidative stress-induced proteome, although proteomic experiments did indicate that Hog1 might be required to ensure the prolonged expression of some proteins during recovery from H2O2 stress [88]. Loss of Hog1 has been shown to affect respiratory function [89], although it is unclear whether this underlies the sensitivity of hog1Δ cells to ROS. One downstream target of Hog1 regulated by H2O2 stress is the Mkc1 cell integrity MAPK. Mkc1 is rapidly phosphorylated in response to H2O2 stress in a Hog1-dependent mechanism, although Mkc1 is not required for cell survival in response to H2O2 stress [90]. In addition, the Sko1 transcription factor is a target of the Hog1 SAPK in C. albicans, as this becomes phosphorylated following stress in a Hog1-dependent manner [91]. However, consistent with Hog1 not playing a major role in regulating oxidative stress-induced gene expression, the H2O2-induced transcriptome is not dependent on Sko1 [92]. Thus, in C. albicans, Hog1 regulation of the oxidative stress response must involve targets in addition to Mkc1 and Sko1 (Figure 2).


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 the Hog1 SAPK. In response to H2O2, Hog1 becomes rapidly phosphorylated and accumulates in the nucleus, and C. albicans cells lacking Hog1 are sensitive to oxidative stress. Proteins required for H2O2-induced activation of Hog1 are shown in green. These include the response regulator Ssk1 (but no other two-component protein), the redox sensitive antioxidants Tsa1 and Trx1, and the mitochondria biogenesis factor Fzo1. Following H2O2-induced activation, Hog1 phosphorylates the Mkc1 MAPK. However, cells lacking Mkc1 are not sensitive to oxidative stress, suggesting that an, as yet, unknown Hog1 substrate(s), mediates oxidative stress resistance.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00142-f002: H2O2-induced activation of the Hog1 SAPK. In response to H2O2, Hog1 becomes rapidly phosphorylated and accumulates in the nucleus, and C. albicans cells lacking Hog1 are sensitive to oxidative stress. Proteins required for H2O2-induced activation of Hog1 are shown in green. These include the response regulator Ssk1 (but no other two-component protein), the redox sensitive antioxidants Tsa1 and Trx1, and the mitochondria biogenesis factor Fzo1. Following H2O2-induced activation, Hog1 phosphorylates the Mkc1 MAPK. However, cells lacking Mkc1 are not sensitive to oxidative stress, suggesting that an, as yet, unknown Hog1 substrate(s), mediates oxidative stress resistance.
Mentions: Stress-activated MAPKs are conserved signalling molecules that promote the ability of cells to adapt to environmental change [82]. They are components of a three-tiered core signalling module that comprises the SAPK itself, a MAP kinase kinase (MAPKK) and a MAPKK kinase (MAPKKK). Activation of the MAPKKK results in the phosphorylation and activation of the MAPKK, which, in turn, culminates in the phosphorylation of the SAPK on conserved threonine and tyrosine residues located within the TGY motif in the phosphorylation lip of the catalytic domain. This induces the activation and nuclear accumulation of the kinase [83] and the proline-directed phosphorylation of Ser/Thr residues on diverse substrates, including transcription factors, kinases, cell cycle regulators and membrane proteins, thus eliciting appropriate cellular responses. In C. albicans, Hog1 is robustly phosphorylated and rapidly accumulates in the nucleus following exposure of cells to H2O2 [33]. In addition, cells lacking Hog1 display increased sensitivity to a range of ROS, indicating that Hog1 activation is a critical component of the oxidative stress response in C. albicans [84,85]. Interestingly, Hog1 is only activated following exposure of C. albicans cells to relatively high levels of H2O2 compared to the analogous Sty1 SAPK in the model yeast, S. pombe. This may reflect an adaption of this pathogenic fungus to restrict Hog1 activation to ROS-rich environments during infection [85]. Despite the increased H2O2 sensitivity exhibited by hog1Δ cells and significant phosphorylation of Hog1 in response to H2O2, transcript profiling experiments revealed that Hog1 is largely dispensable for H2O2-induced gene expression [33]. Although a small subset of H2O2-responsive genes were identified that showed Hog1-dependent induction, subsequent analysis failed to identify any genes coding for proteins with known antioxidant functions [33]. This is in contrast with S. pombe, where Sty1 is required for the activation of the core stress genes in response to H2O2, including genes encoding important antioxidants, such as catalase and glutathione peroxidase [86]. What, therefore, is the role of Hog1 in the C. albicans oxidative stress response if it is not required for the induction of antioxidant gene expression? One possibility is that Hog1 contributes to the oxidative stress response at a post-transcriptional level in C. albicans. Indeed, the S. pombe Sty1 SAPK has been shown to interact with translation factors [87]. However, Hog1 does not play a major role in regulating the oxidative stress-induced proteome, although proteomic experiments did indicate that Hog1 might be required to ensure the prolonged expression of some proteins during recovery from H2O2 stress [88]. Loss of Hog1 has been shown to affect respiratory function [89], although it is unclear whether this underlies the sensitivity of hog1Δ cells to ROS. One downstream target of Hog1 regulated by H2O2 stress is the Mkc1 cell integrity MAPK. Mkc1 is rapidly phosphorylated in response to H2O2 stress in a Hog1-dependent mechanism, although Mkc1 is not required for cell survival in response to H2O2 stress [90]. In addition, the Sko1 transcription factor is a target of the Hog1 SAPK in C. albicans, as this becomes phosphorylated following stress in a Hog1-dependent manner [91]. However, consistent with Hog1 not playing a major role in regulating oxidative stress-induced gene expression, the H2O2-induced transcriptome is not dependent on Sko1 [92]. Thus, in C. albicans, Hog1 regulation of the oxidative stress response must involve targets in addition to Mkc1 and Sko1 (Figure 2).

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