The Role of Secretory Pathways in Candida albicans Pathogenesis

Rollenhagen, Christiane; Mamtani, Sahil; Ma, Dakota; Dixit, R.; Eszterhas, Susan K.; Lee, Samuel A.

doi:10.3390/jof6010026

Cited by 23 publications

(25 citation statements)

References 368 publications

(558 reference statements)

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“…It was interesting to observe an increment in the protein levels at the cell wall of the null mutant strain, and a similar observation was reported for C. albicans mutants with defects in the N-linked mannosylation pathway [31]. It has been described that the canonical secretory pathway is not the only one involved in the transportation of proteins outside the Candida cell [57]. We hypothesize that this increment in the cell wall protein content in the kex2Δ null mutant strains is therefore due to the activation of noncanonical protein secretory pathways, as a compensatory mechanism to overcome the defect in the classical protein secretory pathway.…”

Section: Discussionsupporting

confidence: 69%

Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells

Gómez-Gaviria

Lozoya-Pérez

Staniszewska

et al. 2020

JoF

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The secretory pathway in Candida albicans involves the protein translocation into the lumen of the endoplasmic reticulum and transport to the Golgi complex, where proteins undergo posttranslational modifications, including glycosylation and proteolysis. The Golgi-resident Kex2 protease is involved in such processing and disruption of its encoding gene affected virulence and dimorphism. These previous studies were performed using cells without URA3 or with URA3 ectopically placed into the KEX2 locus. Since these conditions are known to affect the cellular fitness and the host–fungus interaction, here we generated a kex2Δ null mutant strain with URA3 placed into the neutral locus RPS1. The characterization of this strain showed defects in the cell wall composition, with a reduction in the N-linked mannan content, and the increment in the levels of O-linked mannans, chitin, and β-glucans. The defects in the mannan content are likely linked to changes in Golgi-resident enzymes, as the α-1,2-mannosyltransferase and α-1,6-mannosyltransferase activities were incremented and reduced, respectively. The mutant cells also showed reduced ability to stimulate cytokine production and phagocytosis by human mononuclear cells and macrophages, respectively. Collectively, these data showed that loss of Kex2 affected the cell wall composition, the protein glycosylation pathways, and interaction with innate immune cells.

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Section: Discussionsupporting

confidence: 69%

Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells

Gómez-Gaviria

Lozoya-Pérez

Staniszewska

et al. 2020

JoF

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“…In the secretory pathway of C. albicans , proteins are translocated to the ER for a variety of processes, such as folding and glycosylation. Following movement through the Golgi and secretory vesicles, proteins are further transported to various destinations, including the cell wall or the cell exterior [ 61 ]. Therefore, the UPR is essential not only for controlling protein quality but also for maintaining normal secretory function [ 62 ].…”

Section: Resultsmentioning

confidence: 99%

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

Hsu

Liao

Chang

et al. 2021

IJMS

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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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“…In clinical isolates of H. werneckii the enrichment of genes in the ‘vesicle localization’ category may be related to modulation of the switching between yeast and filamentous growth, a process important for fungal pathogenesis that is associated with vesicle transport [ 91 ]. Enrichment of genes in the ‘spliceosomal complex assembly’ category may be related to the importance of splicing regulation during fungal pathogenesis, discussed by Sesma [ 92 ], and enrichment of genes in the ‘homologous recombination’ category may be important for genome plasticity, which is often observed during infection [ 93 ].…”

Section: Discussionmentioning

confidence: 99%

Seven Years at High Salinity—Experimental Evolution of the Extremely Halotolerant Black Yeast Hortaea werneckii

Gostinčar

Stajich

Kejžar

et al. 2021

JoF

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The experimental evolution of microorganisms exposed to extreme conditions can provide insight into cellular adaptation to stress. Typically, stress-sensitive species are exposed to stress over many generations and then examined for improvements in their stress tolerance. In contrast, when starting with an already stress-tolerant progenitor there may be less room for further improvement, it may still be able to tweak its cellular machinery to increase extremotolerance, perhaps at the cost of poorer performance under non-extreme conditions. To investigate these possibilities, a strain of extremely halotolerant black yeast Hortaea werneckii was grown for over seven years through at least 800 generations in a medium containing 4.3 M NaCl. Although this salinity is well above the optimum (0.8–1.7 M) for the species, the growth rate of the evolved H. werneckii did not change in the absence of salt or at high concentrations of NaCl, KCl, sorbitol, or glycerol. Other phenotypic traits did change during the course of the experimental evolution, including fewer multicellular chains in the evolved strains, significantly narrower cells, increased resistance to caspofungin, and altered melanisation. Whole-genome sequencing revealed the occurrence of multiple aneuploidies during the experimental evolution of the otherwise diploid H. werneckii. A significant overrepresentation of several gene groups was observed in aneuploid regions. Taken together, these changes suggest that long-term growth at extreme salinity led to alterations in cell wall and morphology, signalling pathways, and the pentose phosphate cycle. Although there is currently limited evidence for the adaptive value of these changes, they offer promising starting points for future studies of fungal halotolerance.

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The Role of Secretory Pathways in Candida albicans Pathogenesis

Cited by 23 publications

References 368 publications

Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells

Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells

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

Seven Years at High Salinity—Experimental Evolution of the Extremely Halotolerant Black Yeast Hortaea werneckii

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