tivation on medium with cellulose as sole carbon source, consistent with the induction of
key UPR target genes, such as bip-1, pdi-1,
and calnexin (Benz et al. 2014). Deletion of the
hac-1 gene results in the inability to efficiently
degrade cellulose and suppression of growth on
medium containing Avicel (microcrystalline
cellulose) as carbon source (MontenegroMontero et al. 2015). In contrast to A. niger,
the absence of hac-1 did affect neither vegetative growth nor resistance to cell wall stressinducing drugs (Montenegro-Montero et al.
2015). Using a set of more 527 mutant strains,
carrying individual deletions of genes implicated in the ER stress response, identified 249
genes important for ER stress resistance, of
which 100 were so far uncharacterized, including several potential regulators important for
lignocellulase secretion. Deletion of hac-1 or
ire-1 does not affect expression of lignocellulase
genes in response to sensing of cellulose, but
severely affects the secretion of enzymatically
active proteins (Fan et al. 2015). Hence, activation of the UPR provides the intracellular infrastructure important for efficient secretion of
lignocellulolytic enzymes and utilization of cellulose as carbon source. Further profiling of
single-gene deletion strains identified the sterol
regulatory element-binding protein (SREBP)
pathway as an important regulator of protein
secretion under cellulolytic conditions. The
SREBP pathway regulates ergosterol synthesis
in response to hypoxic conditions (Bien and
Espenshade 2010; Robichon and Dugail 2007).
Deletion of the SREBP pathway components
tul-1 and dsc-1, the predicted homologs of S.
pombe dsc1 and dsc2 (Defective in SREBP
Cleavage) that mediate cleavage and activation
of Sre1 in response to hypoxia, results in
strongly increased protein secretion in
response to cellulose but not sucrose or xylan
(Reilly et al. 2015). Deletion of further SREBP
pathway components consistently derepressed
genes involved in the ER stress response and
increased secretion of cellulolytic enzymes.
Inactivation of the SREBP pathway suppressed
the reduced cellulase production of hac-1
mutant strains, revealing a regulatory interplay
between both pathways in adapting the secretory pathway during cellulolytic growth (Qin
et al. 2017).
VI. Conclusion and Outlook
The UPR is a central pathway in eukaryotes
that counteracts ER stress but also compensates
and interacts with a plethora of other stressassociated signaling pathways providing
increased cellular robustness (Thibault et al.
2011). While the main theme of UPR function
is widely conserved, we are at the beginning of
understanding how the divergent lifestyles of
fungi ranging from saprotrophically growing
filamentous fungi over to biotrophic plant
pathogens require specific adaptations of the
UPR. The emerging picture of how signal integration and crosstalk between different cellular
pathways such as the UPR, ERAD, autophagy,
but also developmental control and matingtype signaling is achieved provides important
means to uncover the detailed contribution of
the UPR in fungal pathogenesis and to develop
innovative strategies for unfolding the full
potential of the UPR in biotechnological backgrounds.
Acknowledgements We acknowledge Niko Pinter for
support in figure preparation. We acknowledge funding
of our research by the Deutsche Forschungsgemeinschaft and the IRTG 2172 PRoTECT.
References
Adhikari H, Vadaie N, Chow J, Caccamise LM, Chavel
CA, Li B, Bowitch A, Stefan CJ, Cullen PJ (2015)
Role of the unfolded protein response in regulating the mucin-dependent filamentous-growth
mitogen-activated protein kinase pathway. Mol
Cell Biol 35:1414–1432
Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, Clavaud C, Paris S, Brakhage AA,
Kaveri SV, Romani L, Latge JP (2009) Surface
hydrophobin prevents immune recognition of airborne fungal spores. Nature 460:1117–1121
Al-Sheikh H, Watson AJ, Lacey GA, Punt PJ, MacKenzie
DA, Jeenes DJ, Pakula T, Penttila M, Alcocer MJ,
Archer DB (2004) Endoplasmic reticulum stress
leads to the selective transcriptional downregula68
R. Harting and K. Heimel
key UPR target genes, such as bip-1, pdi-1,
and calnexin (Benz et al. 2014). Deletion of the
hac-1 gene results in the inability to efficiently
degrade cellulose and suppression of growth on
medium containing Avicel (microcrystalline
cellulose) as carbon source (MontenegroMontero et al. 2015). In contrast to A. niger,
the absence of hac-1 did affect neither vegetative growth nor resistance to cell wall stressinducing drugs (Montenegro-Montero et al.
2015). Using a set of more 527 mutant strains,
carrying individual deletions of genes implicated in the ER stress response, identified 249
genes important for ER stress resistance, of
which 100 were so far uncharacterized, including several potential regulators important for
lignocellulase secretion. Deletion of hac-1 or
ire-1 does not affect expression of lignocellulase
genes in response to sensing of cellulose, but
severely affects the secretion of enzymatically
active proteins (Fan et al. 2015). Hence, activation of the UPR provides the intracellular infrastructure important for efficient secretion of
lignocellulolytic enzymes and utilization of cellulose as carbon source. Further profiling of
single-gene deletion strains identified the sterol
regulatory element-binding protein (SREBP)
pathway as an important regulator of protein
secretion under cellulolytic conditions. The
SREBP pathway regulates ergosterol synthesis
in response to hypoxic conditions (Bien and
Espenshade 2010; Robichon and Dugail 2007).
Deletion of the SREBP pathway components
tul-1 and dsc-1, the predicted homologs of S.
pombe dsc1 and dsc2 (Defective in SREBP
Cleavage) that mediate cleavage and activation
of Sre1 in response to hypoxia, results in
strongly increased protein secretion in
response to cellulose but not sucrose or xylan
(Reilly et al. 2015). Deletion of further SREBP
pathway components consistently derepressed
genes involved in the ER stress response and
increased secretion of cellulolytic enzymes.
Inactivation of the SREBP pathway suppressed
the reduced cellulase production of hac-1
mutant strains, revealing a regulatory interplay
between both pathways in adapting the secretory pathway during cellulolytic growth (Qin
et al. 2017).
VI. Conclusion and Outlook
The UPR is a central pathway in eukaryotes
that counteracts ER stress but also compensates
and interacts with a plethora of other stressassociated signaling pathways providing
increased cellular robustness (Thibault et al.
2011). While the main theme of UPR function
is widely conserved, we are at the beginning of
understanding how the divergent lifestyles of
fungi ranging from saprotrophically growing
filamentous fungi over to biotrophic plant
pathogens require specific adaptations of the
UPR. The emerging picture of how signal integration and crosstalk between different cellular
pathways such as the UPR, ERAD, autophagy,
but also developmental control and matingtype signaling is achieved provides important
means to uncover the detailed contribution of
the UPR in fungal pathogenesis and to develop
innovative strategies for unfolding the full
potential of the UPR in biotechnological backgrounds.
Acknowledgements We acknowledge Niko Pinter for
support in figure preparation. We acknowledge funding
of our research by the Deutsche Forschungsgemeinschaft and the IRTG 2172 PRoTECT.
References
Adhikari H, Vadaie N, Chow J, Caccamise LM, Chavel
CA, Li B, Bowitch A, Stefan CJ, Cullen PJ (2015)
Role of the unfolded protein response in regulating the mucin-dependent filamentous-growth
mitogen-activated protein kinase pathway. Mol
Cell Biol 35:1414–1432
Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, Clavaud C, Paris S, Brakhage AA,
Kaveri SV, Romani L, Latge JP (2009) Surface
hydrophobin prevents immune recognition of airborne fungal spores. Nature 460:1117–1121
Al-Sheikh H, Watson AJ, Lacey GA, Punt PJ, MacKenzie
DA, Jeenes DJ, Pakula T, Penttila M, Alcocer MJ,
Archer DB (2004) Endoplasmic reticulum stress
leads to the selective transcriptional downregula68
R. Harting and K. Heimel