highly similar to the XBP1 binding site in
humans (Yamamoto et al. 2004). Importantly,
the Hac1 homolog Cib1 (Clp1 interacting bZIP
1) in U. maydis can functionally replace Hac1 in
S. cerevisiae (Heimel et al. 2013), and the Cterminal extension of Cib1 mediates the interaction with the developmental regulator Clp1
(Clampless 1), by which the developmental program and a modulated UPR interact to control
fungal pathogenesis (Heimel et al. 2013, 2010a,
b; Pinter et al. 2019).
In higher eukaryotes, XBP1 forms homodimers but also heterodimeric complexes with
ATF6 (Byrd and Brewer 2012). Gcn4 (General
Control Nonderepressible 4), the major regulator of the amino acid starvation responses
(Cross-Pathway Control), is required for
expression of the majority of Hac1-regulated
UPR targets in S. cerevisiae, and both pathways
are connected by bidirectional functional interactions (Herzog et al. 2013; Patil et al. 2004).
Moreover, both proteins are regulated in their
stability by Srb10 (Suppressor of RNA polymerase B 10)-mediated phosphorylation and Cdc4
(Cell Division Cycle 4)-mediated ubiquitylation
(Pal et al. 2007; Chi et al. 2001). Similarly, the
interaction between U. maydis Cib1 and Clp1
proteins reduces Cib1 phosphorylation but
promotes increased stability of both proteins
(Pinter et al. 2019). In contrast to the formation
of the stable Cib1/Clp1 complex, a direct protein interaction between Gcn4 and Hac1 has not
been observed.
III. The UPR in Fungal Pathogens
Human, animal, and plant hosts react to infectious threats by upregulating their defense
mechanisms, including an increase of the
body temperature, the focused generation of
reactive oxygen species (ROS), as well as the
induction of programmed cell death to prevent
colonization by fungal pathogens. The ability of
adapting intracellular pathways to the constant
changes fungal pathogens are exposed to during interactions with challenging host environments is therefore a key determinant of fungal
virulence. The UPR has been studied in different human and plant pathogenic fungi and is of
central importance to infect and colonize the
host organism and cause disease. A high capacity for protein secretion is pivotal for shaping
the host environment in support of fungal
infection including mobilization of nutrient
sources and suppression of the plant immune
system by secreted effector proteins. The
underlying mechanism and functions of the
UPR in fungal virulence appear to be common
with respect to ER stress resistance, but also
involve specific adaptations and functions that
are connected to lifestyle and host organisms.
Here, an overview on the distinct requirements
for the UPR in disease development of human
and plant pathogenic fungi will be provided.
A. The UPR in Human Pathogenic Fungi
Fungal pathogens infecting humans and animals rely on the ability to adapt their growth
to the host environment like the body temperature, reduced oxygen supply, or altered nutrient
availability and on mechanisms providing
effective shielding from the host immune system. Functionality of the UPR is associated with
various virulence-related traits including thermotolerance, stress resistance, antifungal drug
resistance, and secretory activity in major
human fungal pathogens such as Aspergillus
fumigatus, Candida albicans, Candida glabrata, and the Cryptococcus species complex
(Krishnan and Askew 2014, Richie et al.
2011b, a, Cheon et al. 2014, Glazier and Panepinto 2014, Miyazaki and Kohno 2014, Raj et al.
2015). In addition, the UPR is induced and
important during morphological responses
that are connected to disease development
(Wimalasena et al. 2008; Jung et al. 2016; Monteiro et al. 2009).
1. Aspergillus fumigatus
Aspergillus fumigatus is an ascomycetous
saprotrophic filamentous fungus commonly
found in the soil and in compost heaps, growing on decaying organic matter and thus promoting flux of the carbon and nitrogen cycle
(Fang and Latge 2018). Conidiospores, regu3 Genetics of the Unfolded Protein Response in Fungi
55
humans (Yamamoto et al. 2004). Importantly,
the Hac1 homolog Cib1 (Clp1 interacting bZIP
1) in U. maydis can functionally replace Hac1 in
S. cerevisiae (Heimel et al. 2013), and the Cterminal extension of Cib1 mediates the interaction with the developmental regulator Clp1
(Clampless 1), by which the developmental program and a modulated UPR interact to control
fungal pathogenesis (Heimel et al. 2013, 2010a,
b; Pinter et al. 2019).
In higher eukaryotes, XBP1 forms homodimers but also heterodimeric complexes with
ATF6 (Byrd and Brewer 2012). Gcn4 (General
Control Nonderepressible 4), the major regulator of the amino acid starvation responses
(Cross-Pathway Control), is required for
expression of the majority of Hac1-regulated
UPR targets in S. cerevisiae, and both pathways
are connected by bidirectional functional interactions (Herzog et al. 2013; Patil et al. 2004).
Moreover, both proteins are regulated in their
stability by Srb10 (Suppressor of RNA polymerase B 10)-mediated phosphorylation and Cdc4
(Cell Division Cycle 4)-mediated ubiquitylation
(Pal et al. 2007; Chi et al. 2001). Similarly, the
interaction between U. maydis Cib1 and Clp1
proteins reduces Cib1 phosphorylation but
promotes increased stability of both proteins
(Pinter et al. 2019). In contrast to the formation
of the stable Cib1/Clp1 complex, a direct protein interaction between Gcn4 and Hac1 has not
been observed.
III. The UPR in Fungal Pathogens
Human, animal, and plant hosts react to infectious threats by upregulating their defense
mechanisms, including an increase of the
body temperature, the focused generation of
reactive oxygen species (ROS), as well as the
induction of programmed cell death to prevent
colonization by fungal pathogens. The ability of
adapting intracellular pathways to the constant
changes fungal pathogens are exposed to during interactions with challenging host environments is therefore a key determinant of fungal
virulence. The UPR has been studied in different human and plant pathogenic fungi and is of
central importance to infect and colonize the
host organism and cause disease. A high capacity for protein secretion is pivotal for shaping
the host environment in support of fungal
infection including mobilization of nutrient
sources and suppression of the plant immune
system by secreted effector proteins. The
underlying mechanism and functions of the
UPR in fungal virulence appear to be common
with respect to ER stress resistance, but also
involve specific adaptations and functions that
are connected to lifestyle and host organisms.
Here, an overview on the distinct requirements
for the UPR in disease development of human
and plant pathogenic fungi will be provided.
A. The UPR in Human Pathogenic Fungi
Fungal pathogens infecting humans and animals rely on the ability to adapt their growth
to the host environment like the body temperature, reduced oxygen supply, or altered nutrient
availability and on mechanisms providing
effective shielding from the host immune system. Functionality of the UPR is associated with
various virulence-related traits including thermotolerance, stress resistance, antifungal drug
resistance, and secretory activity in major
human fungal pathogens such as Aspergillus
fumigatus, Candida albicans, Candida glabrata, and the Cryptococcus species complex
(Krishnan and Askew 2014, Richie et al.
2011b, a, Cheon et al. 2014, Glazier and Panepinto 2014, Miyazaki and Kohno 2014, Raj et al.
2015). In addition, the UPR is induced and
important during morphological responses
that are connected to disease development
(Wimalasena et al. 2008; Jung et al. 2016; Monteiro et al. 2009).
1. Aspergillus fumigatus
Aspergillus fumigatus is an ascomycetous
saprotrophic filamentous fungus commonly
found in the soil and in compost heaps, growing on decaying organic matter and thus promoting flux of the carbon and nitrogen cycle
(Fang and Latge 2018). Conidiospores, regu3 Genetics of the Unfolded Protein Response in Fungi
55