Candida albicans Sfp1 Is Involved in the Cell Wall and Endoplasmic Reticulum Stress Responses Induced by Human Antimicrobial Peptide LL-37

Candida albicans is a commensal fungus of humans but can cause infections, particularly in immunocompromised individuals, ranging from superficial to life-threatening systemic infections. The cell wall is the outermost layer of C. albicans that interacts with the host environment. Moreover, antimicrobial peptides (AMPs) are important components in innate immunity and play crucial roles in host defense. Our previous studies showed that the human AMP LL-37 binds to the cell wall of C. albicans, alters the cell wall integrity (CWI) and affects cell adhesion of this pathogen. In this study, we aimed to further investigate the molecular mechanisms underlying the C. albicans response to LL-37. We found that LL-37 causes cell wall stress, activates unfolded protein response (UPR) signaling related to the endoplasmic reticulum (ER), induces ER-derived reactive oxygen species and affects protein secretion. Interestingly, the deletion of the SFP1 gene encoding a transcription factor reduced C. albicans susceptibility to LL-37, which is cell wall-associated. Moreover, in the presence of LL-37, deletion of SFP1 attenuated the UPR pathway, upregulated oxidative stress responsive (OSR) genes and affected bovine serum albumin (BSA) degradation by secreted proteases. Therefore, these findings suggested that Sfp1 positively regulates cell wall integrity and ER homeostasis upon treatment with LL-37 and shed light on pathogen-host interactions.

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Endoplasmic reticulum-derived reactive oxygen species (ROS) is involved in toxicity of cell wall stress to Candida albicans

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2016.09.014 ◽

2016 ◽

Vol 99 ◽

pp. 572-583 ◽

Cited By ~ 19

Author(s):

Qilin Yu ◽

Bing Zhang ◽

Jianrong Li ◽

Biao Zhang ◽

Honggang Wang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Cell Wall ◽

Candida Albicans ◽

Reactive Oxygen ◽

Wall Stress ◽

Oxygen Species ◽

Cell Wall Stress

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Endoplasmic Reticulum α-Glycosidases of Candida albicans Are Required for N Glycosylation, Cell Wall Integrity, and Normal Host-Fungus Interaction

Eukaryotic Cell ◽

10.1128/ec.00350-07 ◽

2007 ◽

Vol 6 (12) ◽

pp. 2184-2193 ◽

Cited By ~ 83

Author(s):

Héctor M. Mora-Montes ◽

Steven Bates ◽

Mihai G. Netea ◽

Diana F. Díaz-Jiménez ◽

Everardo López-Romero ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Wall ◽

Candida Albicans ◽

Systemic Infection ◽

Cell Wall Integrity ◽

Yeast Cells ◽

Chain Elongation ◽

Cell Wall Integrity Pathway ◽

Oligosaccharide Processing ◽

Host Fungus

ABSTRACT The cell surface of Candida albicans is enriched in highly glycosylated mannoproteins that are involved in the interaction with the host tissues. N glycosylation is a posttranslational modification that is initiated in the endoplasmic reticulum (ER), where the Glc3Man9GlcNAc2 N-glycan is processed by α-glucosidases I and II and α1,2-mannosidase to generate Man8GlcNAc2. This N-oligosaccharide is then elaborated in the Golgi to form N-glycans with highly branched outer chains rich in mannose. In Saccharomyces cerevisiae, CWH41, ROT2, and MNS1 encode for α-glucosidase I, α-glucosidase II catalytic subunit, and α1,2-mannosidase, respectively. We disrupted the C. albicans CWH41, ROT2, and MNS1 homologs to determine the importance of N-oligosaccharide processing on the N-glycan outer-chain elongation and the host-fungus interaction. Yeast cells of Cacwh41Δ, Carot2Δ, and Camns1Δ null mutants tended to aggregate, displayed reduced growth rates, had a lower content of cell wall phosphomannan and other changes in cell wall composition, underglycosylated β-N-acetylhexosaminidase, and had a constitutively activated PKC-Mkc1 cell wall integrity pathway. They were also attenuated in virulence in a murine model of systemic infection and stimulated an altered pro- and anti-inflammatory cytokine profile from human monocytes. Therefore, N-oligosaccharide processing by ER glycosidases is required for cell wall integrity and for host-fungus interactions.

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Hph1p and Hph2p, Novel Components of Calcineurin-Mediated Stress Responses in Saccharomyces cerevisiae

Eukaryotic Cell ◽

10.1128/ec.3.3.695-704.2004 ◽

2004 ◽

Vol 3 (3) ◽

pp. 695-704 ◽

Cited By ~ 62

Author(s):

Victoria L Heath ◽

Sidney L. Shaw ◽

Sharmili Roy ◽

Martha S. Cyert

Keyword(s):

Saccharomyces Cerevisiae ◽

Endoplasmic Reticulum ◽

Cell Wall ◽

Stress Responses ◽

Wall Stress ◽

Sequence Motif ◽

Alkaline Ph ◽

Cell Wall Stress ◽

High Concentrations

ABSTRACT Calcineurin is a Ca2+- and calmodulin-dependent protein phosphatase that plays a key role in animal and yeast physiology. In the yeast Saccharomyces cerevisiae, calcineurin is required for survival during several environmental stresses, including high concentrations of Na+, Li+, and Mn2+ ions and alkaline pH. One role of calcineurin under these conditions is to activate gene expression through its regulation of the Crz1p transcription factor. We have identified Hph1p as a novel substrate of calcineurin. HPH1 (YOR324C) and its homolog HPH2 (YAL028W) encode tail-anchored integral membrane proteins that interact with each other in the yeast two-hybrid assay and colocalize to the endoplasmic reticulum. Hph1p and Hph2p serve redundant roles in promoting growth under conditions of high salinity, alkaline pH, and cell wall stress. Calcineurin modifies the distribution of Hph1p within the endoplasmic reticulum and is required for full Hph1p activity in vivo. Furthermore, calcineurin directly dephosphorylates Hph1p and interacts with it through a sequence motif in Hph1p, PVIAVN. This motif is related to calcineurin docking sites in other substrates, such as NFAT and Crz1p, and is required for regulation of Hph1p by calcineurin. In contrast, Hph2p neither interacts with nor is dephosphorylated by calcineurin. Ca2+-induced Crz1p-mediated transcription is unaffected in hph1Δ hph2Δ mutants, and genetic analyses indicate that HPH1/HPH2 and CRZ1 act in distinct pathways downstream of calcineurin. Thus, Hph1p and Hph2p are components of a novel Ca2+- and calcineurin-regulated response required to promote growth under conditions of high Na+, alkaline pH, and cell wall stress.

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The P-type ATPase Spf1 is required for endoplasmic reticulum functions and cell wall integrity in Candida albicans

International Journal of Medical Microbiology ◽

10.1016/j.ijmm.2013.05.003 ◽

2013 ◽

Vol 303 (5) ◽

pp. 257-266 ◽

Cited By ~ 14

Author(s):

Qilin Yu ◽

Xiaohui Ding ◽

Bing Zhang ◽

Ning Xu ◽

Xinxin Cheng ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Wall ◽

Candida Albicans ◽

Cell Wall Integrity ◽

P Type

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UDP-glucose 4, 6-dehydratase Activity Plays an Important Role in Maintaining Cell Wall Integrity and Virulence of Candida albicans

PLoS Pathogens ◽

10.1371/journal.ppat.1002384 ◽

2011 ◽

Vol 7 (11) ◽

pp. e1002384 ◽

Cited By ~ 10

Author(s):

Manimala Sen ◽

Bhavin Shah ◽

Srabanti Rakshit ◽

Vijender Singh ◽

Bhavna Padmanabhan ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Cell Wall Integrity ◽

Dehydratase Activity

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Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine

Infection and Immunity ◽

10.1128/iai.01612-14 ◽

2014 ◽

Vol 82 (10) ◽

pp. 4405-4413 ◽

Cited By ~ 32

Author(s):

Sarah E. Davis ◽

Alex Hopke ◽

Steven C. Minkin ◽

Anthony E. Montedonico ◽

Robert T. Wheeler ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

De Novo ◽

Invasive Disease ◽

Innate Immune ◽

Dependent Manner ◽

Content Type ◽

Immune Effector ◽

Host Interactions ◽

Innate Immune Effector

ABSTRACTThe virulence ofCandida albicansin a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase geneCHO1(i.e.,cho1Δ/Δ) eliminates PS and blocks thede novopathway for PE biosynthesis. In addition, thecho1Δ/Δ mutant's ability to cause invasive disease is severely compromised. Thecho1Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-typeC. albicans, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. Thecho1Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS inC. albicansresults in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.

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