Yeast AP-1 like transcription factors (Yap) and stress response: a current overview

Abstract

Yeast adaptation to stress has been extensively studied. It involves large reprogramming of genome expression operated by many, more or less specific, transcription factors. Here, we review our current knowledge on the function of the eight Yap transcription factors (Yap1 to Yap8) in Saccharomyces cerevisiae, which were shown to be involved in various stress responses. More precisely, Yap1 is activated under oxidative stress, Yap2/Cad1 under cadmium, Yap4/Cin5 and Yap6 under osmotic shock, Yap5 under iron overload and Yap8/Arr1 by arsenic compounds. Yap3 and Yap7 seem to be involved in hydroquinone and nitrosative stresses, respectively. The data presented in this article illustrate how much knowledge on the function of these Yap transcription factors is advanced. The evolution of the Yap family and its roles in various pathogenic and non-pathogenic fungal species is discussed in the last section.

Keywords: Yap factors; bZIP; cis-elements; stress; yeast.

Figure 1. FIGURE 1: Structural features of the Yap family DNA binding domain.

The sequences of the eight Yap DNA binding domains (i.e. the basic region of the bZIP motif) are compared with the equivalent region of Gcn4, the classical yeast AP-1 factor, used as an outgroup. A green background highlights the positions, whose physico-chemical properties are conserved in the Yap family. The most conserved residues are in bold. The Yap8 specific residues are in blue. The Yap1 amino-acids which were predicted to contact DNA based on structural studies [12, 140] have been underlined by a black box. The Gcn4 residues involved in DNA interaction are highlighted by pink boxes. The rooted tree and the multiple alignment were obtained from ClustalW (https://www.genome.jp/tools-bin/clustalw), using the bZIP sequences and the 100 flanking amino-acids.

Figure 2. FIGURE 2: Schematic representation of Yap1 activation.

Yap1 has two distinct molecular sensors: one for hydrogen peroxide (H₂O₂) and the other for thiol-reactive compounds (see description in the text). In the first panel is represented the shuttling of Yap1 between the nucleus and cytoplasm, occurring under physiological conditions, entering the nucleus by Pse1 importin and exiting the nucleus by exportin Crm1. In the second panel is depicted the activation of Yap1 by H₂O₂, which is dependent on Hyr1/Gxp3/Orp1 and Ybp1 proteins. H₂O₂ induces the formation of a disulfide bond between Cys303 and Cys598 of Yap1, preventing the recognition of the nuclear export signal (NES) by Crm1 (represented in red the activated Yap1). In the third panel is depicted the activation of Yap1 by thiol-reactive agents. These compounds bind to Cys598, Cys620 and Cys629, thereby preventing the recognition of the NES by Crm1 (in purple the activated Yap1). In both cases, the conformational change leads to Yap1 accumulation in the nucleus and posterior gene activation.

Figure 3. FIGURE 3: Schematic representation of the Yap5 involvement in the cellular response to iron-overload.

In upper panel is represented the cellular response to low levels of iron (“low iron” in the figure) where the Aft1 transcription factor is responsible for the activation of the iron regulon. In the lower panel is represented the role of Yap5 when cells are exposed to iron excess conditions (“high iron” in the figure). Yap5 activates the expression of CCC1, coding for a vacuolar iron transporter, and of TYW1, encoding a cytosolic Fe-S cluster protein. Additionally, it activates the expression of GRX4 gene, coding for a glutathione-dependent oxidoreductase, leading to Aft1 accumulation in the cytoplasm.

Figure 4. FIGURE 4: Schematic representation of the Yap1 and Yap8 involvement in arsenic adaptation.

The phosphate transporters, Pho84 and Pho87, take up arsenate. Arsenite can enter the cells through hexose transporters, Hxt, and the aquaglyceroporin, Fps1. Upon arsenic exposure, Yap8 recognizes and binds a specific YRE sequence, TGATTAATAATCA, depicted as Y8RE. Then, it interacts with the mediator complex, via the tail subunit Med2, which is essential for the full activation of its target genes, ACR2 and ACR3 (for details see text). Arsenite is imported into the vacuole, in conjugation with glutathione, by Ycf1, which is regulated by Yap1. Furthermore, Yap1 activates antioxidant response and Fe-S cluster biogenesis genes, to mitigate the ROS and the disruption of Fe-S clusters, generated by arsenic.

Figure 5. FIGURE 5: Evolution of the Yap family in fungi.

The Yap proteins have been indicated for seven fungal species: the hemiascomycetes S. cerevisiae, C. glabrata, K. lactis and C. albicans, the euascomycete A. nudilans, the archaeascomycetes S. pombe and the basidiomycete C. neoformans. The tree on the left is just a schematic representation of the phylogenetic relationships between these species. The whole genome duplication event is indicated by a black star. The remarkable protein domains (squares) and the described function (circles) are indicated for each Yap. The color code is indicated at the bottom of the figure.