ER stress response mechanisms in the pathogenic yeast Candida glabrata and their roles in virulence

Abstract

The maintenance of endoplasmic reticulum (ER) homeostasis is critical for numerous aspects of cell physiology. Eukaryotic cells respond to the accumulation of misfolded proteins in the ER (ER stress) by activating the unfolded protein response (UPR), an intracellular signaling pathway that adjusts the folding capacity of the ER. Recent studies of several pathogenic fungi have revealed that the UPR is important for antifungal resistance and virulence; therefore, the pathway has attracted much attention as a potential therapeutic target. While the UPR is highly conserved among eukaryotes, our group recently discovered that the pathogenic yeast Candida glabrata lacks the typical fungal UPR, but possesses alternative mechanisms to cope with ER stress. This review summarizes how C. glabrata responds to ER stress and discusses the impacts of ER quality control systems on antifungal resistance and virulence.

Keywords: Candida glabrata; Hac1; Ire1; Slt2; antifungal resistance; calcineurin; endoplasmic reticulum stress; regulated Ire1-dependent decay; unfolded protein response; virulence.

Figure 1. Signaling pathways involved in the ER stress response in C. glabrata. The classic UPR pathway mediated by Ire1-Hac1 signaling (dotted lines) is not conserved in C. glabrata. In response to ER stress, Ire1 induces RIDD to degrade ER-localized mRNAs in an Ire1 nuclease-dependent fashion, whereas calcineurin regulates both Crz1-dependent and Crz1-independent pathways. In addition, Slt2 is required for the ER stress response independently of its downstream transcription factors Rlm1 and SBF (Swi4/Swi6). Ire1, calcineurin, and Slt2 have also been implicated indirectly in antifungal resistance and virulence in C. glabrata. HAC1^u, uninduced form of HAC1; HAC1ⁱ, induced form of HAC1; SBF, Swi4/Swi6 cell cycle box-binding factor; UPR, unfolded protein response; RIDD, regulated Ire1-dependent decay; CCS, calcium cell survival; ERSU, ER stress surveillance.