sition. Although virulence has not been directly
assayed, HAC1 deletion mutants fail to induce
hyphal growth, suggesting an important function of the UPR in C. albicans virulence (Wimalasena et al. 2008). Homozygous HAC1 mutants
are not impaired in vegetative growth but show
reduced resistance towards drugs inducing ER
or cell wall stress. Analysis of Hac1-dependent
gene expression in response to DTT or TM
treatment revealed only few genes regulated in
common by Hac1 in C. albicans and S. cerevisiae (Travers et al. 2000). Differentially
expressed
and
Hac1-dependent
genes
include several encoding for adhesins, such
as ALS4, ALS5, ALS12, and ALS10 (AgglutininLike Sequence) (Hoyer 2001), as well as
PMT1, PMT2, and PMT4–6 (Protein O-MannosylTransferase),
encoding
Omannosyltransferases important for adhesin
function (Timpel et al. 1998; Timpel et al. 2000).
Expression of UPR target genes upon ER stress
is supported by the calcineurin effector Rta2
(Resistance To Aminocholesterol 2). Rta2 functions as plasma membrane-localized flippase
involved in sphingolipid long-chain base
release (Jia et al. 2009) and is transcriptionally
induced upon TM treatment (Thomas et al.
2015). Rta2 does not influence abundance of
the spliced HAC1
i mRNA and likely supports
UPR target gene expression in a Hac1independent manner. Consistently, the high
susceptibility of HAC1 and RTA2 deletion
mutants to TM is further increased upon parallel deletion of both genes (Thomas et al. 2015).
The signaling mucin Msb2 (Multicopy Suppression of a Budding defect 2) is a plasma
membrane-localized surface receptor involved
in sensing of and adaptation to hyperosmotic
and cell wall stress (Roman et al. 2009) and
required for antifungal drug resistance, ER
stress resistance, and growth at elevated temperatures (Saraswat et al. 2016). It is moreover
essential for activation of the CEK1 (C. albicans
ERK-like Kinase 1) MAPK (Mitogen-Activated
Protein Kinase) pathway (Roman et al. 2009)
and for transcriptional induction of IRE1,
HAC1, and KAR2 (BIP1) during growth at elevated temperatures (Saraswat et al. 2016). Interestingly, in S. cerevisiae, Ire1 supports cleavage
of Msb2 by regulating the transcriptional
induction of the Msb2 processing protease
Yps1 (YaPSin 1) (Adhikari et al. 2015).
4. Candida glabrata
Similar to C. albicans, Candida glabrata is a
commensal of human mucosal tissue that is
prevalent in immunosuppressed patients and,
based on the high resistance against antifungal
azoles, represents a major threat in clinical settings (Fidel Jr. et al. 1999). In contrast to most
other fungi, the UPR in C. glabrata is mediated
in an Ire1-dependent but Hac1-independent
manner (Miyazaki et al. 2013). Under ER
stress-inducing conditions, no unconventional
splicing of HAC1 mRNA is observed, and
although IRE1 is required for ER stress resistance, the transcriptional response to treatment
with ER stress-inducing drugs is independent
of Ire1, but largely depends on calcineurin signaling and to a smaller extent on the Slt2 (Suppressor of the Lytic phenotype 2) MAPK
signaling pathway (Cell Wall Integrity, CWI).
Interestingly, expression of CgIRE1 in an S.
cerevisiae DIRE1 mutant did not restore ER
stress resistance, whereas expression of
CgHAC1 fully recovered ER stress resistance
of S. cerevisiae DIRE1 and DHAC1 mutants
(Miyazaki et al. 2013). The connection between
ER stress resistance and functionality of the
calcineurin- and Slt2-dependent MAPK signaling pathway is well established in S. cerevisiae
(Bonilla and Cunningham 2003; Bonilla et al.
2002; Chen et al. 2005; Dudgeon et al. 2008). In
C. glabrata Ire1, calcineurin and Slt2 are coordinately required for the ER stress response and
display additive effects on ER stress susceptibility when individual mutations are combined.
While calcineurin and Slt2 are important for
the transcriptional response to ER stress (Miyazaki et al. 2013), Ire1 primarily regulates mRNA
abundance via degradation of ER-associated
mRNAs by RIDD (Hollien et al. 2009) to reduce
ER protein synthesis and decrease the demands
for protein folding in the ER (Miyazaki et al.
2013). IRE1 is critical for virulence of C. glabrata, but in contrast to calcineurin not involved
58
R. Harting and K. Heimel
assayed, HAC1 deletion mutants fail to induce
hyphal growth, suggesting an important function of the UPR in C. albicans virulence (Wimalasena et al. 2008). Homozygous HAC1 mutants
are not impaired in vegetative growth but show
reduced resistance towards drugs inducing ER
or cell wall stress. Analysis of Hac1-dependent
gene expression in response to DTT or TM
treatment revealed only few genes regulated in
common by Hac1 in C. albicans and S. cerevisiae (Travers et al. 2000). Differentially
expressed
and
Hac1-dependent
genes
include several encoding for adhesins, such
as ALS4, ALS5, ALS12, and ALS10 (AgglutininLike Sequence) (Hoyer 2001), as well as
PMT1, PMT2, and PMT4–6 (Protein O-MannosylTransferase),
encoding
Omannosyltransferases important for adhesin
function (Timpel et al. 1998; Timpel et al. 2000).
Expression of UPR target genes upon ER stress
is supported by the calcineurin effector Rta2
(Resistance To Aminocholesterol 2). Rta2 functions as plasma membrane-localized flippase
involved in sphingolipid long-chain base
release (Jia et al. 2009) and is transcriptionally
induced upon TM treatment (Thomas et al.
2015). Rta2 does not influence abundance of
the spliced HAC1
i mRNA and likely supports
UPR target gene expression in a Hac1independent manner. Consistently, the high
susceptibility of HAC1 and RTA2 deletion
mutants to TM is further increased upon parallel deletion of both genes (Thomas et al. 2015).
The signaling mucin Msb2 (Multicopy Suppression of a Budding defect 2) is a plasma
membrane-localized surface receptor involved
in sensing of and adaptation to hyperosmotic
and cell wall stress (Roman et al. 2009) and
required for antifungal drug resistance, ER
stress resistance, and growth at elevated temperatures (Saraswat et al. 2016). It is moreover
essential for activation of the CEK1 (C. albicans
ERK-like Kinase 1) MAPK (Mitogen-Activated
Protein Kinase) pathway (Roman et al. 2009)
and for transcriptional induction of IRE1,
HAC1, and KAR2 (BIP1) during growth at elevated temperatures (Saraswat et al. 2016). Interestingly, in S. cerevisiae, Ire1 supports cleavage
of Msb2 by regulating the transcriptional
induction of the Msb2 processing protease
Yps1 (YaPSin 1) (Adhikari et al. 2015).
4. Candida glabrata
Similar to C. albicans, Candida glabrata is a
commensal of human mucosal tissue that is
prevalent in immunosuppressed patients and,
based on the high resistance against antifungal
azoles, represents a major threat in clinical settings (Fidel Jr. et al. 1999). In contrast to most
other fungi, the UPR in C. glabrata is mediated
in an Ire1-dependent but Hac1-independent
manner (Miyazaki et al. 2013). Under ER
stress-inducing conditions, no unconventional
splicing of HAC1 mRNA is observed, and
although IRE1 is required for ER stress resistance, the transcriptional response to treatment
with ER stress-inducing drugs is independent
of Ire1, but largely depends on calcineurin signaling and to a smaller extent on the Slt2 (Suppressor of the Lytic phenotype 2) MAPK
signaling pathway (Cell Wall Integrity, CWI).
Interestingly, expression of CgIRE1 in an S.
cerevisiae DIRE1 mutant did not restore ER
stress resistance, whereas expression of
CgHAC1 fully recovered ER stress resistance
of S. cerevisiae DIRE1 and DHAC1 mutants
(Miyazaki et al. 2013). The connection between
ER stress resistance and functionality of the
calcineurin- and Slt2-dependent MAPK signaling pathway is well established in S. cerevisiae
(Bonilla and Cunningham 2003; Bonilla et al.
2002; Chen et al. 2005; Dudgeon et al. 2008). In
C. glabrata Ire1, calcineurin and Slt2 are coordinately required for the ER stress response and
display additive effects on ER stress susceptibility when individual mutations are combined.
While calcineurin and Slt2 are important for
the transcriptional response to ER stress (Miyazaki et al. 2013), Ire1 primarily regulates mRNA
abundance via degradation of ER-associated
mRNAs by RIDD (Hollien et al. 2009) to reduce
ER protein synthesis and decrease the demands
for protein folding in the ER (Miyazaki et al.
2013). IRE1 is critical for virulence of C. glabrata, but in contrast to calcineurin not involved
58
R. Harting and K. Heimel