in yeasts (Bonilla and Cunningham 2003; Chen
et al. 2005; Scrimale et al. 2009) and filamentous
fungi (Colabardini et al. 2010; Malavazi et al.
2014; Yin et al. 2016). Deletion mutants of the
genes encoding homologs of Hac1 and Ire1
show increased susceptibility towards cell wall
stress-inducing agents in A. brassicicola, M.
oryzae, and A. fumigatus and C. neoformans
(Cheon et al. 2011; Joubert et al. 2011; Kong
et al. 2015; Tang et al. 2015), suggesting widely
conserved interactions between UPR and CWI
pathways. Conversely, key players involved in
CWI signaling, including Slt2, are consistently
required for ER stress resistance in C. albicans
(Chen et al. 2005), C. glabrata (Miyazaki et al.
2013), and S. cerevisiae (Chen et al. 2005). Since
UPR signaling affects vegetative growth and
proper hyphal development and controls
expression of genes important for cell wall synthesis (Joubert et al. 2011; Travers et al. 2000),
the bidirectional activation of either pathway
might establish a compensatory mechanism to
generate distinct responses to various stressinducing conditions.
D. UPR and MAPK Signaling
MAPK signaling pathways are key players in a
wide variety of cellular adaptation processes
and mediate the response to altered osmolality
and light, cell wall integrity, nutrient deprivation, oxidative stress, and the presence of mating partners or compatible cells for fusion by
anastomosis (Bahn and Jung 2013; Fleissner
and Herzog 2016; Garrido-Bazan et al. 2018;
Gonzalez-Rubio et al. 2019; Yu et al. 2016).
Besides the previously elaborated crosstalk
between UPR and CWI pathways (see Sect. IV.
C.), additional regulatory interactions between
the UPR and MAPK-controlled signaling pathways have been described. In C. neoformans,
increased UPR activity is observed under
osmotic stress, and the high-osmolarity glycerol (HOG) pathway is important for ER stress
resistance upon exposure of increased TM concentrations (Cheon et al. 2011). In addition,
deletion of IRE1 results in defects in sexual
mating and a compensatory response of the
pheromone MAPK cascade, leading to strongly
increased expression of the pheromone precursor gene MFa1 (Jung et al. 2016). Since the
mating defect is connected to erroneous localization of the pheromone transporter Ste6, the
connection between Ire1 and the pheromone
MAPK pathway is likely indirect (Jung et al.
2016). In U. maydis, expression of the intronless cib1
s mRNA leads to constitutive activation
of the UPR and reduced expression of the b
mating-type locus genes bE and bW and the
major regulator downstream of the bheterodimer Rbf1. This inhibitory effect of the
UPR is reflected by reduced formation of infectious filaments and, as a consequence, fungal
virulence (Heimel et al. 2013). Systematic analysis of crosstalk between the UPR and the pheromone MAPK pathway revealed strongly
reduced phosphorylation of the MAPK Kpp2
in strains with constitutively active UPR, resulting in the UPR-dependent inhibition of the
morphological and transcriptional response to
pheromone (Schmitz et al. 2019b). The dualspecificity phosphatase Rok1 regulates activity
of the mating-type signaling pathway by dephosphorylating Kpp2 and the partially redundant
MAPK Kpp6. Deletion of rok1 leads to hypervirulence of U. maydis, whereas overexpression
reduces virulence (Di Stasio et al. 2009). The
UPR promotes increased Rok1 activity, and
deletion of rok1 fully restores Kpp2 phosphorylation, formation of infectious filaments, and
virulence, suggesting that the feedback regulation between the UPR and MAPK affects the
virulence potential of U. maydis and ensures
fungal biotrophy (Schmitz et al. 2019b)
(Fig. 3.4).
E. UPR and Hypoxia
Hypoxic conditions suppress oxidation of
membrane lipids and induce the activation of
a compensatory response regulated by the sterol regulatory element-binding protein
(SREBP) (Shimano and Sato 2017). Membrane
aberrancies induced by inositol depletion activate the ER stress sensor Ire1 by a mechanism
that is distinct from canonical activation via
unfolded proteins (Promlek et al. 2011). The
ability to grow under hypoxic conditions is
3 Genetics of the Unfolded Protein Response in Fungi
65
et al. 2005; Scrimale et al. 2009) and filamentous
fungi (Colabardini et al. 2010; Malavazi et al.
2014; Yin et al. 2016). Deletion mutants of the
genes encoding homologs of Hac1 and Ire1
show increased susceptibility towards cell wall
stress-inducing agents in A. brassicicola, M.
oryzae, and A. fumigatus and C. neoformans
(Cheon et al. 2011; Joubert et al. 2011; Kong
et al. 2015; Tang et al. 2015), suggesting widely
conserved interactions between UPR and CWI
pathways. Conversely, key players involved in
CWI signaling, including Slt2, are consistently
required for ER stress resistance in C. albicans
(Chen et al. 2005), C. glabrata (Miyazaki et al.
2013), and S. cerevisiae (Chen et al. 2005). Since
UPR signaling affects vegetative growth and
proper hyphal development and controls
expression of genes important for cell wall synthesis (Joubert et al. 2011; Travers et al. 2000),
the bidirectional activation of either pathway
might establish a compensatory mechanism to
generate distinct responses to various stressinducing conditions.
D. UPR and MAPK Signaling
MAPK signaling pathways are key players in a
wide variety of cellular adaptation processes
and mediate the response to altered osmolality
and light, cell wall integrity, nutrient deprivation, oxidative stress, and the presence of mating partners or compatible cells for fusion by
anastomosis (Bahn and Jung 2013; Fleissner
and Herzog 2016; Garrido-Bazan et al. 2018;
Gonzalez-Rubio et al. 2019; Yu et al. 2016).
Besides the previously elaborated crosstalk
between UPR and CWI pathways (see Sect. IV.
C.), additional regulatory interactions between
the UPR and MAPK-controlled signaling pathways have been described. In C. neoformans,
increased UPR activity is observed under
osmotic stress, and the high-osmolarity glycerol (HOG) pathway is important for ER stress
resistance upon exposure of increased TM concentrations (Cheon et al. 2011). In addition,
deletion of IRE1 results in defects in sexual
mating and a compensatory response of the
pheromone MAPK cascade, leading to strongly
increased expression of the pheromone precursor gene MFa1 (Jung et al. 2016). Since the
mating defect is connected to erroneous localization of the pheromone transporter Ste6, the
connection between Ire1 and the pheromone
MAPK pathway is likely indirect (Jung et al.
2016). In U. maydis, expression of the intronless cib1
s mRNA leads to constitutive activation
of the UPR and reduced expression of the b
mating-type locus genes bE and bW and the
major regulator downstream of the bheterodimer Rbf1. This inhibitory effect of the
UPR is reflected by reduced formation of infectious filaments and, as a consequence, fungal
virulence (Heimel et al. 2013). Systematic analysis of crosstalk between the UPR and the pheromone MAPK pathway revealed strongly
reduced phosphorylation of the MAPK Kpp2
in strains with constitutively active UPR, resulting in the UPR-dependent inhibition of the
morphological and transcriptional response to
pheromone (Schmitz et al. 2019b). The dualspecificity phosphatase Rok1 regulates activity
of the mating-type signaling pathway by dephosphorylating Kpp2 and the partially redundant
MAPK Kpp6. Deletion of rok1 leads to hypervirulence of U. maydis, whereas overexpression
reduces virulence (Di Stasio et al. 2009). The
UPR promotes increased Rok1 activity, and
deletion of rok1 fully restores Kpp2 phosphorylation, formation of infectious filaments, and
virulence, suggesting that the feedback regulation between the UPR and MAPK affects the
virulence potential of U. maydis and ensures
fungal biotrophy (Schmitz et al. 2019b)
(Fig. 3.4).
E. UPR and Hypoxia
Hypoxic conditions suppress oxidation of
membrane lipids and induce the activation of
a compensatory response regulated by the sterol regulatory element-binding protein
(SREBP) (Shimano and Sato 2017). Membrane
aberrancies induced by inositol depletion activate the ER stress sensor Ire1 by a mechanism
that is distinct from canonical activation via
unfolded proteins (Promlek et al. 2011). The
ability to grow under hypoxic conditions is
3 Genetics of the Unfolded Protein Response in Fungi
65