Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans

Area of Science:

• Molecular biology
• Mycology
• Drug resistance mechanisms

Background:

• * *Candida albicans* develops resistance to azole drugs during chronic candidiasis treatment.
• * Gain-of-function (GOF) mutations in the transcription factor Tac1 lead to overexpression of drug efflux pumps (Cdr1, Cdr2), conferring fluconazole resistance.
• * The precise mechanism of Tac1 hyperactivation by GOF mutations remains unclear.

Purpose of the Study:

• * To elucidate the mechanism by which GOF mutations hyperactivate the transcription factor Tac1.
• * To investigate the role of the Tac1 transcriptional activation domain (TAD) and the Mediator complex in azole resistance.
• * To identify potential biomarkers for Tac1 hyperactivation.

Main Methods:

• * Characterization of the Tac1 transcriptional activation domain (TAD).
• * Analysis of Tac1 function in full-length and truncated forms.
• * Investigation of Mediator complex recruitment to target gene promoters.
• * Assessment of Tac1 phosphorylation as a biomarker.

Main Results:

• * A TAD was identified at the C terminus of Tac1; GOF mutations within it did not enhance activation independently.
• * Negative regulation by the Tac1 middle region is crucial for GOF mutation-mediated activation.
• * Hyperactivated Tac1 recruits the Mediator complex to the *CDR1* promoter.
• * Tac1 target gene activation and azole resistance depend on the Tac1 TAD and Mediator tail module.
• * Tac1 hyperactivation correlates with Mediator-dependent phosphorylation.

Conclusions:

• * The Tac1 TAD and Mediator complex are essential for azole resistance in *C. albicans*.
• * Mediator-dependent phosphorylation of Tac1 serves as a potential biomarker for hyperactivation.
• * Understanding Mediator's role offers therapeutic intervention strategies against drug-resistant fungal infections.