| Autor: |
Oneissi, Mazen, Cruz, Melissa R., Ramírez-Zavala, Bernardo, Lindemann-Perez, Elena, Morschhäuser, Joachim, Garsin, Danielle A., Perez, J. Christian |
| Předmět: |
|
| Zdroj: |
PLoS Pathogens; 9/28/2023, Vol. 19 Issue 9, p1-23, 23p |
| Abstrakt: |
The signals that denote mammalian host environments and dictate the activation of signaling pathways in human-associated microorganisms are often unknown. The transcription regulator Rtg1/3 in the human fungal pathogen Candida albicans is a crucial determinant of host colonization and pathogenicity. Rtg1/3's activity is controlled, in part, by shuttling the regulator between the cytoplasm and nucleus of the fungus. The host signal(s) that Rtg1/3 respond(s) to, however, have remained unclear. Here we report that neutrophil-derived reactive oxygen species (ROS) direct the subcellular localization of this C. albicans transcription regulator. Upon engulfment of Candida cells by human or mouse neutrophils, the regulator shuttles to the fungal nucleus. Using genetic and chemical approaches to disrupt the neutrophils' oxidative burst, we establish that the oxidants produced by the NOX2 complex–but not the oxidants generated by myeloperoxidase–trigger Rtg1/3's migration to the nucleus. Furthermore, screening a collection of C. albicans kinase deletion mutants, we implicate the MKC1 signaling pathway in the ROS-dependent regulation of Rtg1/3 in this fungus. Finally, we show that Rtg1/3 contributes to C. albicans virulence in the nematode Caenorhabditis elegans in an ROS-dependent manner as the rtg1 and rtg3 mutants display virulence defects in wild-type but not in ROS deficient worms. Our findings establish NOX2-derived ROS as a key signal that directs the activity of the pleiotropic fungal regulator Rtg1/3. Author summary: Candida albicans is a ubiquitous fungus of humans. It inhabits various compartments of the human body including oral cavity and gastrointestinal tract. C. albicans is also a leading cause of life-threatening disseminated infections. As with other human-associated microorganisms, the exact nature of the signals sensed by this fungus inside host tissues is often unknown. We have established that the C. albicans regulatory system Rtg1/3 is pivotal for the fungus to colonize and proliferate inside the mammalian host, implying that the regulator's activity may respond to one or more cues that denote the host environment. In this study, we sought to pinpoint the cue(s) and signaling molecules that direct the regulator's activity inside the host. We report that host-derived reactive oxygen species determine the activation of this regulator by promoting its translocation from the cytoplasm to the nucleus of the fungus. As a signal that dictates the activity of Rtg1/3, reactive oxygen species may concomitantly direct the activation of additional pathways required for Candida to endure in the host because Rtg1/3 constitutes a central node of a rather large regulatory network driving mammalian host colonization. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
|
Nepřihlášeným uživatelům se plný text nezobrazuje |
K zobrazení výsledku je třeba se přihlásit.
|
