UPR is required for proliferation in planta,
UPR activity inhibits pathogenic growth before
plant infection by reducing phosphorylation of
the pheromone MAPK Kpp2 (Heimel et al.
2013; Schmitz et al. 2019b). This effect is
mediated by the dual-specificity phosphatase
Rok1 (Regulator of Kpp2 1). Activity of Rok1
is inversely correlated with virulence of U. maydis as the absence of Rok1 activity results in
hypervirulence and failure to sustain fungal
biotrophy, whereas increased activity results
in reduced virulence (Di Stasio et al. 2009).
Since activity of Rok1 is regulated by the UPR,
ER stress levels appear to be connected to the
control of fungal biotrophy including negative
feedback control of mating-type regulated
effector gene expression (for overview see
Fig. 3.4).
IV. Connections and Interplay
Between the UPR and Other
Signaling Pathways
The response to ER stress is functionally
connected to a plethora of different pathways
that altogether foster resistance to environmental changes and thereby contribute to fitness
and resilience of fungi. The interaction between
the UPR and autophagy, the cell wall integrity
(CWI) pathway, ER-associated degradation
pathway (ERAD), hypoxia response, and
MAPK signaling pathways is realized on different levels, including transcriptional control,
posttranslational modifications, or proteinprotein interactions. The constantly expanding
data on these interactions suggest the existence
of widely conserved crosstalk but also specific
connections shared only between fungi with
similar lifestyles or ecological niches. In the
following we summarize the current knowledge
on the interconnections of the different pathways and UPR.
A. UPR and ERAD
The ER-associated degradation (ERAD) pathway is an integral part of the ER quality control
machinery, constantly removing terminally
misfolded and potentially toxic proteins from
the ER for proteasomal degradation in the cytoplasm. Several interrelated ERAD pathways
exist in eukaryotes. The ERAD-L pathway specifically contributes to the degradation of substrates with luminal lesions, the ERAD-C
pathway for degradation of substrates with
cytosolic lesions, and the ERAD-M pathway
mediates degradation of substrates with lesions
in transmembrane domains (Thibault and Ng
2012). ERAD complexes are targeted to the ER
membrane and consist of core E3 ubiquitin
ligases (see also Fig. 3.1) (Doa10 in ERAD-C
and Hrd1 in ERAD-L and M) and associated
proteins. Doa10 (Degradation Of Alpha 10)
forms two distinct complexes with Cue1 (Coupling of Ubiquitin conjugation to ER degradation 1) and Ubc7 (Ubiquitin-Conjugating
enzyme 7) or with Cdc48 (Cell Division Cycle
48), Npl4 (Nuclear Protein Localization 4),
Ufd1 (Ubiquitin Fusion Degradation protein
1), and Ubx2 (Ubiquitin regulatory X 2). Hrd1
associates with Hrd3, Der1, Yos9 (Yeast OS-9
homolog), and Usa1 (U1-Snp1 Associating 1)
(Carvalho et al. 2006). Several ER and cytosolic
chaperones are associated with ERAD function
including Kar2/Bip1, Scj1 (S. Cerevisiae DnaJ
1), Jem1 (DnaJ-like protein of the ER Membrane 1), and Pdi1 in the ER lumen (Gillece
et al. 1999; Grubb et al. 2012; Nishikawa et al.
2001; Silberstein et al. 1998; Thibault et al. 2011)
and Ydj1 (Yeast DnaJ 1), Hlj1 (Homologous to
E. coli dnaJ protein 1), and Hsp70 in the cytosol
(Huyer et al. 2004, Park et al. 2007, Vembar
et al. 2009). Recognition of terminally misfolded protein for degradation via ERAD is
mediated by a glycan timer cascade. If folding
and glycosylation of substrate proteins is repetitively erroneous, mannosidase activity of the
Htm1-Pdi1 complex generates a substrate recognition site for Yos9, which in turn delivers
the substrate for Hrd1-dependent ubiquitylation and retro-translocation into the cytosol
(Bhamidipati et al. 2005; Buschhorn et al.
2004; Gauss et al. 2011; Izawa et al. 2012).
ERAD and UPR pathway components display
compensatory interactions, and abrogation of
both pathways leads to drastically increased
stress sensitivity (Thibault et al. 2011). Several
62
R. Harting and K. Heimel
UPR activity inhibits pathogenic growth before
plant infection by reducing phosphorylation of
the pheromone MAPK Kpp2 (Heimel et al.
2013; Schmitz et al. 2019b). This effect is
mediated by the dual-specificity phosphatase
Rok1 (Regulator of Kpp2 1). Activity of Rok1
is inversely correlated with virulence of U. maydis as the absence of Rok1 activity results in
hypervirulence and failure to sustain fungal
biotrophy, whereas increased activity results
in reduced virulence (Di Stasio et al. 2009).
Since activity of Rok1 is regulated by the UPR,
ER stress levels appear to be connected to the
control of fungal biotrophy including negative
feedback control of mating-type regulated
effector gene expression (for overview see
Fig. 3.4).
IV. Connections and Interplay
Between the UPR and Other
Signaling Pathways
The response to ER stress is functionally
connected to a plethora of different pathways
that altogether foster resistance to environmental changes and thereby contribute to fitness
and resilience of fungi. The interaction between
the UPR and autophagy, the cell wall integrity
(CWI) pathway, ER-associated degradation
pathway (ERAD), hypoxia response, and
MAPK signaling pathways is realized on different levels, including transcriptional control,
posttranslational modifications, or proteinprotein interactions. The constantly expanding
data on these interactions suggest the existence
of widely conserved crosstalk but also specific
connections shared only between fungi with
similar lifestyles or ecological niches. In the
following we summarize the current knowledge
on the interconnections of the different pathways and UPR.
A. UPR and ERAD
The ER-associated degradation (ERAD) pathway is an integral part of the ER quality control
machinery, constantly removing terminally
misfolded and potentially toxic proteins from
the ER for proteasomal degradation in the cytoplasm. Several interrelated ERAD pathways
exist in eukaryotes. The ERAD-L pathway specifically contributes to the degradation of substrates with luminal lesions, the ERAD-C
pathway for degradation of substrates with
cytosolic lesions, and the ERAD-M pathway
mediates degradation of substrates with lesions
in transmembrane domains (Thibault and Ng
2012). ERAD complexes are targeted to the ER
membrane and consist of core E3 ubiquitin
ligases (see also Fig. 3.1) (Doa10 in ERAD-C
and Hrd1 in ERAD-L and M) and associated
proteins. Doa10 (Degradation Of Alpha 10)
forms two distinct complexes with Cue1 (Coupling of Ubiquitin conjugation to ER degradation 1) and Ubc7 (Ubiquitin-Conjugating
enzyme 7) or with Cdc48 (Cell Division Cycle
48), Npl4 (Nuclear Protein Localization 4),
Ufd1 (Ubiquitin Fusion Degradation protein
1), and Ubx2 (Ubiquitin regulatory X 2). Hrd1
associates with Hrd3, Der1, Yos9 (Yeast OS-9
homolog), and Usa1 (U1-Snp1 Associating 1)
(Carvalho et al. 2006). Several ER and cytosolic
chaperones are associated with ERAD function
including Kar2/Bip1, Scj1 (S. Cerevisiae DnaJ
1), Jem1 (DnaJ-like protein of the ER Membrane 1), and Pdi1 in the ER lumen (Gillece
et al. 1999; Grubb et al. 2012; Nishikawa et al.
2001; Silberstein et al. 1998; Thibault et al. 2011)
and Ydj1 (Yeast DnaJ 1), Hlj1 (Homologous to
E. coli dnaJ protein 1), and Hsp70 in the cytosol
(Huyer et al. 2004, Park et al. 2007, Vembar
et al. 2009). Recognition of terminally misfolded protein for degradation via ERAD is
mediated by a glycan timer cascade. If folding
and glycosylation of substrate proteins is repetitively erroneous, mannosidase activity of the
Htm1-Pdi1 complex generates a substrate recognition site for Yos9, which in turn delivers
the substrate for Hrd1-dependent ubiquitylation and retro-translocation into the cytosol
(Bhamidipati et al. 2005; Buschhorn et al.
2004; Gauss et al. 2011; Izawa et al. 2012).
ERAD and UPR pathway components display
compensatory interactions, and abrogation of
both pathways leads to drastically increased
stress sensitivity (Thibault et al. 2011). Several
62
R. Harting and K. Heimel