of ERAD components hrdC and derA (Conesa
et al. 2002; Lombrana et al. 2004; Ngiam et al.
2000), (Carvalho et al. 2011; Punt et al. 1998).
Only in few cases, the yields of produced proteins were significantly increased. Overexpression of calnexin (clxA) resulted in a fivefold
increased yield of manganese peroxidase and
deletion of hrdA in a sixfold increased yield of
glucoamylase-glucuronidase (Carvalho et al.
2011; Conesa et al. 2002). Interestingly, several
genes encoding secretory proteins are
repressed under secretion stress (RESS) (AlSheikh et al. 2004). A cis-acting element, located
in the promoter of the secreted glucoamylase
encoding gene glaA, is critical for RESS of glaA.
A potential negative effect of the UPR on glaA
expression might be indirect and connected to
the repression of the AmyR transcription factor, a known regulator of glaA and other secretory proteins (Carvalho et al. 2012). An
additional compensatory response to ER stress
is deduced from the observation of reduced
ribosome occupancy of mRNAs encoding
secreted proteins under DTT-induced ER stress
conditions (Guillemette et al. 2007), contrasting
the results of a similar approach in A. fumigatus
revealing an overall increase of ribosome association of mRNAs (Krishnan and Askew 2014).
B. Trichoderma reesei
The filamentous ascomycete Trichoderma reesei has an enormous intrinsic capacity for cellulose degradation and was identified as the
causal organism degrading the cotton tents of
GI stationed in Southeast Asia during the Second World War (Merivuori et al. 1985; Montenecourt et al. 1981). Similar to A. niger, the
protein disulfide isomerase encoding gene
pdi1 and the ER chaperone encoding gene
bip1 were identified as ER stress induced (Saloheimo et al. 1999; Pakula et al. 2003). Genomewide comparison of ER stress-mediated gene
expression in T. reesei and S. cerevisiae revealed
a set of commonly regulated UPR genes, but
also identified the specific upregulation of cpc1,
encoding the homolog of yeast Gcn4, the key
regulator of the response to amino acid imbalance (cross-pathway control) and of the histone
gene H4 (Arvas et al. 2006). High-level secretion of cellulases is connected to increased UPR
activity, and overexpression of the UPR regulator Hac1 or the ER chaperone Bip1 supports
increased cellulase production (Gao et al. 2018).
Inhibition of protein transport through the
secretory pathway by brefeldin A or DTT treatment results in Hac1-mediated induction of
general UPR components but strongly
decreased expression of genes encoding xylanases and cellulases by RESS (Pakula et al.
2003). Attempts to harness strains overexpressing the ER stress sensor Ire1 for increased
production of Phlebia radiata laccase were
unsuccessful, as expression of the UPR genes
pdi1 and bip1 was only modestly increased. By
contrast, deletion mutants of the Ire1 repressing phosphatase Ptc2 displayed strongly
increased induction of the UPR. The resulting
effects on the production of secreted proteins
were not determined (Valkonen et al. 2004).
The lectin chaperone calnexin, as an integral
part of the ER quality control machinery, is
required for efficient secretion of CBH1 (Cellobiohydrolase I). Targeted mutation of Nglycosylated aa residues in the catalytic domain
reduces thermostability of CBH1 and activates
UPR signaling (Qi et al. 2014).
C. Neurospora crassa
Neurospora crassa has a long-standing tradition
as model organism for the investigation of
fundamental genetic and cellular processes
(“one gene-one enzyme” hypothesis, quelling
and RNAi, mechanism of the circadian clock,
and principles of epigenetic gene control) (Aramayo and Selker 2013; Roche et al. 2014). More
recently, N. crassa has become of considerable
interest with respect to fungal biotechnology,
such as the production of biofuels. The production of biofuels requires the efficient degradation of plant biomass by carbohydrate active
enzymes (CAZymes). System-wide analysis of
the response to various complex polysaccharides found in plant cell walls identified the hac1 gene as being specifically induced during cul3 Genetics of the Unfolded Protein Response in Fungi
67
et al. 2002; Lombrana et al. 2004; Ngiam et al.
2000), (Carvalho et al. 2011; Punt et al. 1998).
Only in few cases, the yields of produced proteins were significantly increased. Overexpression of calnexin (clxA) resulted in a fivefold
increased yield of manganese peroxidase and
deletion of hrdA in a sixfold increased yield of
glucoamylase-glucuronidase (Carvalho et al.
2011; Conesa et al. 2002). Interestingly, several
genes encoding secretory proteins are
repressed under secretion stress (RESS) (AlSheikh et al. 2004). A cis-acting element, located
in the promoter of the secreted glucoamylase
encoding gene glaA, is critical for RESS of glaA.
A potential negative effect of the UPR on glaA
expression might be indirect and connected to
the repression of the AmyR transcription factor, a known regulator of glaA and other secretory proteins (Carvalho et al. 2012). An
additional compensatory response to ER stress
is deduced from the observation of reduced
ribosome occupancy of mRNAs encoding
secreted proteins under DTT-induced ER stress
conditions (Guillemette et al. 2007), contrasting
the results of a similar approach in A. fumigatus
revealing an overall increase of ribosome association of mRNAs (Krishnan and Askew 2014).
B. Trichoderma reesei
The filamentous ascomycete Trichoderma reesei has an enormous intrinsic capacity for cellulose degradation and was identified as the
causal organism degrading the cotton tents of
GI stationed in Southeast Asia during the Second World War (Merivuori et al. 1985; Montenecourt et al. 1981). Similar to A. niger, the
protein disulfide isomerase encoding gene
pdi1 and the ER chaperone encoding gene
bip1 were identified as ER stress induced (Saloheimo et al. 1999; Pakula et al. 2003). Genomewide comparison of ER stress-mediated gene
expression in T. reesei and S. cerevisiae revealed
a set of commonly regulated UPR genes, but
also identified the specific upregulation of cpc1,
encoding the homolog of yeast Gcn4, the key
regulator of the response to amino acid imbalance (cross-pathway control) and of the histone
gene H4 (Arvas et al. 2006). High-level secretion of cellulases is connected to increased UPR
activity, and overexpression of the UPR regulator Hac1 or the ER chaperone Bip1 supports
increased cellulase production (Gao et al. 2018).
Inhibition of protein transport through the
secretory pathway by brefeldin A or DTT treatment results in Hac1-mediated induction of
general UPR components but strongly
decreased expression of genes encoding xylanases and cellulases by RESS (Pakula et al.
2003). Attempts to harness strains overexpressing the ER stress sensor Ire1 for increased
production of Phlebia radiata laccase were
unsuccessful, as expression of the UPR genes
pdi1 and bip1 was only modestly increased. By
contrast, deletion mutants of the Ire1 repressing phosphatase Ptc2 displayed strongly
increased induction of the UPR. The resulting
effects on the production of secreted proteins
were not determined (Valkonen et al. 2004).
The lectin chaperone calnexin, as an integral
part of the ER quality control machinery, is
required for efficient secretion of CBH1 (Cellobiohydrolase I). Targeted mutation of Nglycosylated aa residues in the catalytic domain
reduces thermostability of CBH1 and activates
UPR signaling (Qi et al. 2014).
C. Neurospora crassa
Neurospora crassa has a long-standing tradition
as model organism for the investigation of
fundamental genetic and cellular processes
(“one gene-one enzyme” hypothesis, quelling
and RNAi, mechanism of the circadian clock,
and principles of epigenetic gene control) (Aramayo and Selker 2013; Roche et al. 2014). More
recently, N. crassa has become of considerable
interest with respect to fungal biotechnology,
such as the production of biofuels. The production of biofuels requires the efficient degradation of plant biomass by carbohydrate active
enzymes (CAZymes). System-wide analysis of
the response to various complex polysaccharides found in plant cell walls identified the hac1 gene as being specifically induced during cul3 Genetics of the Unfolded Protein Response in Fungi
67