Timing Is Everything: The Fungal Circadian Clock as a Master Regulator of Stress Response and Pathogenesis
Abstract
1. Introduction: The Fungal Clock as a Proactive Survival Mechanism
2. The Molecular Architecture of Fungal Timekeeping: Conservation and Divergence
2.1. The Neurospora crassa Paradigm: The FRQ-WCC Oscillator
2.2. Beyond the Paradigm: Clock Diversity Across the Fungal Kingdom
2.3. Entrainment: Synchronizing with the External World
3. Beyond Transcription: Non-Transcriptional and Metabolic Oscillators
4. Circadian Gating of Cellular Defense: Anticipatory Regulation of Stress Responses
4.1. Anticipating Oxidative Threats
4.2. Managing Osmotic and Desiccation Stress
4.3. Adapting to Nutritional Fluctuations
4.4. Responding to Chemical Stress
5. The Chrono-Pathogenesis of Fungal Infections
5.1. Transcriptional Cascades: The WCC as a Master Regulator
5.2. The Temporal Interplay Between Host and Pathogen and the Chrono-Therapeutic Hypothesis
6. Molecular Output Pathways: From Oscillation to Action
6.1. Transcriptional and Epigenetic Control
6.2. Post-Translational Regulation
6.3. Developmental Rhythms: Conidiation and Hyphal Branching
7. Discussion
8. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
FRQ | FREQUENCY |
WCC | WHITE COLLAR COMPLEX |
TTFL | Transcription-Translation Feedback Loop |
ROS | Reactive Oxygen Species |
YROs | Yeast Respiratory Oscillations |
AMF | Arbuscular Mycorrhizal Fungi |
MAPK | Mitogen-Activated Protein Kinase |
PP2A | Protein Phosphatase 2A |
eEF-2 | Eukaryotic Elongation Factor 2 |
ccg | Clock-Controlled Genes |
NTOs | Non-Transcriptional Oscillators |
GCN2 | General Control Nonderepressible 2 |
CPC-1 | Cross-Pathway Control 1 |
SAGA | Spt-Ada-Gcn5 Acetyltransferase (complex) |
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Phylum | Species | Core Oscillator Type | WC-1/WC-2 Homologs (Presence/Function) | FRQ Homolog(s) (Presence/Function) | Primary Entrainment Cue(s) | Key Rhythmic Output(s) | Validation Status | Reference(s) |
---|---|---|---|---|---|---|---|---|
Ascomycota | Neurospora crassa | FRQ/WCC TTFL | Present/positive element, photoreceptor | Present/negative element | Light, temperature | Asexual sporulation (conidiation), stress response, hyphal branching | Experimental | [14] |
Botrytis cinerea | FRQ/WCC TTFL | Present/positive element homologs | Present/negative element, virulence regulator | Light | Virulence, pathogenesis | Experimental | [10,24] | |
Fusarium oxysporum | FRQ/WCC TTFL | Present/positive element homologs essential for virulence | Present/primary negative element essential for virulence | Light, host signals (inferred) | Virulence, toxin production, zinc homeostasis | Experimental | [25] | |
Aspergillus flavus | Non-FRQ (Unknown) | Present/putative | Absent | Light, temperature | Sclerotia development | Experimental | [27] | |
Penicillium claviforme | Unknown | Unknown | Unknown | Light, magnetic field | Coremia formation | Experimental | [28] | |
Saccharomyces cerevisiae | Metabolic NTO (YROs) | Absent | Absent | Temperature, metabolic cycles | Respiratory oscillations, gene expression | Experimental | [35] | |
Schizosaccharomyces pombe | Ultradian Oscillator | Unknown | Unknown | Temperature, signaling pathways | Cell signaling oscillations | Experimental | [36] | |
Arthrobotrys oligospora | Unknown (CryA involved) | Present (putative) | Unknown | Light | Conidiation, Trap formation | Experimental | [26] | |
Rhizoglomus irregulare | FRQ/WCC TTFL (putative) | Present/expressed in symbiotic stages | Present/expressed in symbiotic stages | Host metabolic signals (hypothesized) | Coordination with host (hypothesized) | Genomic/inferred | [39] | |
Basidiomycota | Pellicularia filamentosa | Unknown | Unknown | Unknown | Light (inferred) | Nocturnal basidiospore discharge | Experimental | [31] |
Neonothopanus gardneri | Unknown | Unknown | Unknown | Light, temperature | Bioluminescence (luciferase, luciferin cycling) | Experimental | [32] | |
Mucoromycota | Pilobolus spp. | Unknown | Unknown | Unknown | Light | Sporangium discharge (phototropism) | Experimental | [33] |
Stress/Function | Key Clock-Controlled Gene/Protein | Mechanism of Regulation | Fungal Species | Validation Status | Reference(s) |
---|---|---|---|---|---|
Oxidative Stress | Catalase-1 (cat-1) | Transcriptional regulation by WCC | Neurospora crassa | Directly validated | [52] |
Osmotic Stress | OS-2 (MAPK) | Rhythmic phosphorylation (activation) | Neurospora crassa | Directly validated | [53] |
Osmotic Stress | ccg-1 (osmotic-responsive gene) | Transcriptional regulation downstream of rhythmic OS-2 activation | Neurospora crassa | Directly validated | [55] |
Nutritional Stress | frequency (frq) | Epigenetic (histone acetylation) via GCN2/CPC-1/SAGA pathway | Neurospora crassa | Directly validated | [57] |
Virulence | bcfrq1 (clock core component) | Required for rhythmic virulence | Botrytis cinerea | Directly validated | [24] |
Zinc Starvation | FoZafA (transcription factor) | Rhythmic transcription regulated by the clock | Fusarium oxysporum | Directly validated | [25] |
Toxin Production | FoCzf1 (transcription factor) | Rhythmic transcription regulated by the clock | Fusarium oxysporum | Directly validated | [25] |
Translation | eEF-2 (elongation factor) | Rhythmic phosphorylation downstream of rhythmic OS-2 activation | Neurospora crassa | Directly validated | [71] |
Development | Conidiation and hyphal branching | Rhythmic growth and gene expression | Neurospora crassa, Podospora anserina | Directly validated | [75] |
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Coca-Ruiz, V.; Boy-Ruiz, D. Timing Is Everything: The Fungal Circadian Clock as a Master Regulator of Stress Response and Pathogenesis. Stresses 2025, 5, 47. https://doi.org/10.3390/stresses5030047
Coca-Ruiz V, Boy-Ruiz D. Timing Is Everything: The Fungal Circadian Clock as a Master Regulator of Stress Response and Pathogenesis. Stresses. 2025; 5(3):47. https://doi.org/10.3390/stresses5030047
Chicago/Turabian StyleCoca-Ruiz, Victor, and Daniel Boy-Ruiz. 2025. "Timing Is Everything: The Fungal Circadian Clock as a Master Regulator of Stress Response and Pathogenesis" Stresses 5, no. 3: 47. https://doi.org/10.3390/stresses5030047
APA StyleCoca-Ruiz, V., & Boy-Ruiz, D. (2025). Timing Is Everything: The Fungal Circadian Clock as a Master Regulator of Stress Response and Pathogenesis. Stresses, 5(3), 47. https://doi.org/10.3390/stresses5030047