Sterol uptake control protein 2 (Upc2) (Upc2)

Sterol uptake control protein 2 (Upc2) is a fungal-specific zinc cluster transcription factor that serves as a master regulator of ergosterol biosynthesis and sterol uptake [2, 7]. In pathogenic fungi like Candida albicans, Upc2 responds to sterol depletion—often caused by antifungal drugs like azoles—by binding to sterol response elements (SREs) and upregulating genes such as ERG11, which encodes the target enzyme for azoles [4, 10]. Gain-of-function mutations in Upc2 are a primary driver of clinical azole resistance, leading to constitutive overexpression of the ergosterol pathway and drug efflux pumps [31, 32]. Because the Zn(2)-Cys(6) binuclear cluster domain of Upc2 is unique to fungi and absent in humans, it represents a highly attractive therapeutic target for developing novel antifungals or adjuvants to restore azole sensitivity [25, 37]. Inhibition of Upc2 has been shown to increase susceptibility to multiple classes of antifungal agents and prevent the adaptive transcriptional response that leads to resistance [3, 34].

Other names

Mannoprotein regulation by oxygen protein 4MOX4ECM22CaUpc2ScUpc2Upc2p

Upc2 binds to sterol response elements (SREs) in the promoters of ergosterol biosynthesis genes (such as ERG11 and ERG2) to activate their transcription in response to sterol depletion or antifungal drug stress [2, 7, 33].