valho et al. 2011b). In A. fumigatus deletion of
either hrdA (HRD1) or derA resulted in
decreased virulence only upon parallel deletion
of both genes or in combination with the hacA
deletion (Krishnan et al. 2013; Richie et al.
2011b). By contrast, elimination of central
ERAD components in single, double, or triple
combinations did affect neither ER resistance
nor virulence of U. maydis (Pinter et al. 2019).
Interestingly, resistance against the novel antifungal compound sr7575 requires a functional
ERAD pathway in both S. cerevisiae and A.
fumigatus, suggesting a conserved role of
ERAD in antifungal drug resistance in yeasts
and filamentous fungi (Raj et al. 2015).
B. UPR and Autophagy
The response to ER stress results in restructuring of the secretory pathway and the enlargement of the ER to provide sufficient resources
for accommodation of the upregulated ER protein folding machinery. Autophagy (“selfeating”) is an essential intracellular pathway
required for the recycling of damaged or superfluous intracellular macromolecules ranging
from whole organelles to individual proteins
(Pollack et al. 2009; Reggiori and Klionsky
2013). 42 atg (Autophagy-related) genes were
identified in S. cerevisiae, most of which are
likely conserved but not fully characterized in
filamentous fungi (Voigt and Po ¨ggeler 2013).
Functionality of autophagy is crucial for virulence in many pathogenic fungi (Khalid et al.
2019; Nadal and Gold 2010; Palmer et al. 2008;
Tam et al. 2016; Yin et al. 2019) and for cellular
differentiation of filamentous ascomycetes
(Voigt and Po ¨ggeler 2013). The process of
macroautophagy mediates recycling of bulk
cellular components, whereas selective autophagy accounts for the degradation and recycling of specific cellular components,
including organelles. Autophagy-mediated degradation of the ER, referred to as ER-phagy,
promotes cellular homeostasis by balancing
ER synthesis and degradation. Both macroautophagy and selective autophagy contribute to
ER-phagy and require the core autophagic
machinery, including Atg8 proteins (Bernales
et al. 2006; Lipatova and Segev 2015; Mochida
et al. 2015). Selective ER-phagy is also reported
to, at least in part, function independent of key
atg genes (Schuck et al. 2014). In S. cerevisiae,
expression of ATG8 is induced by ER stress and
the function of Atg8 and other Atg proteins is
required for ER stress resistance (Bernales et al.
2006). By contrast, in C. albicans and A. niger,
the absence of Atg8 does not impact ER resistance (Burggraaf and Ram 2016). Functional
homologs of the S. cerevisiae ER-phagy receptors Atg39 and Atg40, recruiting Atg8 for selective ER-phagy (Mochida et al. 2015), have not
been identified in filamentous fungi. Hence,
connections between autophagy and the UPR
appear to be conserved in fungi, whereas the
extent of crosstalk and interactions between
both pathways likely differs between individual
fungal species.
C. UPR and the Cell Wall Integrity Pathway
Maintenance of cell wall integrity (CWI) is an
active and essential process guiding fungal
morphology and development, but also resistance to antifungal drugs, metabolites, or
organic acids. The CWI is regulated by signal
transduction cascades involving the most
upstream mechanosensory proteins, termed
Wsc1 (cell Wall integrity and Stress response
Component), Wsc2, Wsc3, and Mtl1 (Mid-Two
Like 1) in S. cerevisiae, which are functionally
conserved in filamentous fungi in detecting cell
wall stress (Beauvais et al. 2001; Dichtl et al.
2012; Lesage and Bussey 2006; Levin 2011;
Samantaray et al. 2013). Transmission of the
signal occurs via the Rho1 GTPase, which is
activated by GTP exchange factors (GEFs) and
in turn binds to and activates Pkc1 (Protein
Kinase C). Pkc1 activity promotes MAPKmediated phosphotransfer and activation of
the terminal MAPK, termed Slt2 in S. cerevisiae
and MpkA in aspergilli. MpkA activates the
Rlm1/RlmA (Resistance to Lethality of
MKK1P386 overexpression) transcription factor to alter expression of genes involved in cell
wall synthesis and remodeling (Futagami et al.
2011; Jung and Levin 1999). Crosstalk between
the UPR and CWI pathways has been observed
64
R. Harting and K. Heimel
either hrdA (HRD1) or derA resulted in
decreased virulence only upon parallel deletion
of both genes or in combination with the hacA
deletion (Krishnan et al. 2013; Richie et al.
2011b). By contrast, elimination of central
ERAD components in single, double, or triple
combinations did affect neither ER resistance
nor virulence of U. maydis (Pinter et al. 2019).
Interestingly, resistance against the novel antifungal compound sr7575 requires a functional
ERAD pathway in both S. cerevisiae and A.
fumigatus, suggesting a conserved role of
ERAD in antifungal drug resistance in yeasts
and filamentous fungi (Raj et al. 2015).
B. UPR and Autophagy
The response to ER stress results in restructuring of the secretory pathway and the enlargement of the ER to provide sufficient resources
for accommodation of the upregulated ER protein folding machinery. Autophagy (“selfeating”) is an essential intracellular pathway
required for the recycling of damaged or superfluous intracellular macromolecules ranging
from whole organelles to individual proteins
(Pollack et al. 2009; Reggiori and Klionsky
2013). 42 atg (Autophagy-related) genes were
identified in S. cerevisiae, most of which are
likely conserved but not fully characterized in
filamentous fungi (Voigt and Po ¨ggeler 2013).
Functionality of autophagy is crucial for virulence in many pathogenic fungi (Khalid et al.
2019; Nadal and Gold 2010; Palmer et al. 2008;
Tam et al. 2016; Yin et al. 2019) and for cellular
differentiation of filamentous ascomycetes
(Voigt and Po ¨ggeler 2013). The process of
macroautophagy mediates recycling of bulk
cellular components, whereas selective autophagy accounts for the degradation and recycling of specific cellular components,
including organelles. Autophagy-mediated degradation of the ER, referred to as ER-phagy,
promotes cellular homeostasis by balancing
ER synthesis and degradation. Both macroautophagy and selective autophagy contribute to
ER-phagy and require the core autophagic
machinery, including Atg8 proteins (Bernales
et al. 2006; Lipatova and Segev 2015; Mochida
et al. 2015). Selective ER-phagy is also reported
to, at least in part, function independent of key
atg genes (Schuck et al. 2014). In S. cerevisiae,
expression of ATG8 is induced by ER stress and
the function of Atg8 and other Atg proteins is
required for ER stress resistance (Bernales et al.
2006). By contrast, in C. albicans and A. niger,
the absence of Atg8 does not impact ER resistance (Burggraaf and Ram 2016). Functional
homologs of the S. cerevisiae ER-phagy receptors Atg39 and Atg40, recruiting Atg8 for selective ER-phagy (Mochida et al. 2015), have not
been identified in filamentous fungi. Hence,
connections between autophagy and the UPR
appear to be conserved in fungi, whereas the
extent of crosstalk and interactions between
both pathways likely differs between individual
fungal species.
C. UPR and the Cell Wall Integrity Pathway
Maintenance of cell wall integrity (CWI) is an
active and essential process guiding fungal
morphology and development, but also resistance to antifungal drugs, metabolites, or
organic acids. The CWI is regulated by signal
transduction cascades involving the most
upstream mechanosensory proteins, termed
Wsc1 (cell Wall integrity and Stress response
Component), Wsc2, Wsc3, and Mtl1 (Mid-Two
Like 1) in S. cerevisiae, which are functionally
conserved in filamentous fungi in detecting cell
wall stress (Beauvais et al. 2001; Dichtl et al.
2012; Lesage and Bussey 2006; Levin 2011;
Samantaray et al. 2013). Transmission of the
signal occurs via the Rho1 GTPase, which is
activated by GTP exchange factors (GEFs) and
in turn binds to and activates Pkc1 (Protein
Kinase C). Pkc1 activity promotes MAPKmediated phosphotransfer and activation of
the terminal MAPK, termed Slt2 in S. cerevisiae
and MpkA in aspergilli. MpkA activates the
Rlm1/RlmA (Resistance to Lethality of
MKK1P386 overexpression) transcription factor to alter expression of genes involved in cell
wall synthesis and remodeling (Futagami et al.
2011; Jung and Levin 1999). Crosstalk between
the UPR and CWI pathways has been observed
64
R. Harting and K. Heimel