secondary metabolism is further corroborated
by the application of proteasome inhibitors
such as bortezomib. Proteasome inhibitors
delay germination, appressoria formation, and
host infection processes of the rice blast fungus
M. oryzae (Wang et al. 2011; Oh et al. 2012).
Inhibition of the proteasome resulted in the
identification of several new compounds in
Pleosporales or in the plant pathogen Pestalotiopsis sydowiana (VanderMolen et al. 2014; Xia
et al. 2016). Although the targets of the 26S
proteasome, which coordinate fungal development and secondary metabolism in these specific cases, are still unknown, it seems likely
that they include regulatory proteins with a
limited half-life that interconnect different cellular pathways.
B. Degradation by Autophagy
High protein turnover results in damaged fungal proteasomes, which are degraded in yeasts
and presumably also in filamentous fungi by
self-eating autophagy (Waite et al. 2016; Hoeller and Dikic 2016). This is, besides the proteasomal degradation, the second major
eukaryotic degradation system. It is a highly
organized membrane-trafficking pathway,
specialized for long-lived proteins as well as
quality control for large and heterogeneous cellular material including protein aggregates or
organelles. Malfunction of this conserved process is, e.g., associated to neurodegenerative
diseases in humans as well as impairment of
accurate fungal secondary metabolism and differentiation. Autophagy provides nutrients
during stress conditions, starvation, or transition phases of developmental programs (Voigt
and Po ¨ggeler 2013; Popova et al. 2018, Fig. 8.4).
Fungi produce secondary metabolites, which
directly affect autophagy such as the beneficial
rasfonin from Talaromyces, which reduces different cancer cells by inducing autophagy (Xiao
et al. 2014; Sun et al. 2016).
The targeted engulfment of cellular material by membrane invaginations of the vacuole
is termed microautophagy. Macroautophagy
corresponds to the sequestration of bulk cellular material such as damaged organelles or protein aggregates by de novo formed phagophore,
e.g., during yeast starvation (Li et al. 2012;
Reggiori et al. 2012). Cargo proteins are
engulfed during this process by the double
membrane phagophore, which closes to form
the autophagosome. This compartment fuses
with the fungal vacuole at its outer membrane,
while the inner autophagic body is digested by
the hydrolytic vacuolar milieu. Autophagy can
be either non-selective or selective. Selective
autophagy for the degradation of different cellular organelles, e.g., the pexophagy for defective peroxisomes in Sordaria macrospora,
requires specific cargo receptors (Werner et al.
2019).
Instead of degradation, selective autophagy
pathways can also be used for hydrolytic
enzyme transportation to the vacuole as the
yeast cytoplasm-to-vacuole transport (Cvt)
pathway (Lynch-Day and Klionsky 2010). Fungal secondary metabolism takes place in different cellular compartments such as the
cytoplasm, the peroxisomes, vesicles, or
vacuoles. The transport of enzymes and metabolic compounds or precursors is therefore
often mediated through autophagic pathways.
For instance, aflatoxin production requires a
complex interplay of different autophagic processes. Vesicles bud from mitochondria and
peroxisomes, which deliver precursors and
enzymes to Cvt vesicles containing other
enzymes of the biosynthetic pathway to form
the aflatoxisomes. Aflatoxisomes mediate the
biosynthesis by the transport of active enzymes
as well as compartmentalization by storing different aflatoxin intermediates and the aflatoxin
export to the cell exterior (Chanda et al. 2009;
Roze et al. 2011a).
Autophagy-associated atg genes were first
identified in the unicellular fungus S. cerevisiae.
Until 2016, 42 yeast atg genes were identified
including 18 core genes for autophagosome
formation, which are mostly conserved in filamentous fungi (Wen and Klionsky 2016; Parzych et al. 2018).
In the initiation phase, starvation-induced
autophagy requires an active Atg1 Ser/Thr
kinase complex, which is inhibited under nonstarvation conditions by the active Tor (target
of rapamycin) kinase complex, sensing nitro194
J. Gerke et al.
by the application of proteasome inhibitors
such as bortezomib. Proteasome inhibitors
delay germination, appressoria formation, and
host infection processes of the rice blast fungus
M. oryzae (Wang et al. 2011; Oh et al. 2012).
Inhibition of the proteasome resulted in the
identification of several new compounds in
Pleosporales or in the plant pathogen Pestalotiopsis sydowiana (VanderMolen et al. 2014; Xia
et al. 2016). Although the targets of the 26S
proteasome, which coordinate fungal development and secondary metabolism in these specific cases, are still unknown, it seems likely
that they include regulatory proteins with a
limited half-life that interconnect different cellular pathways.
B. Degradation by Autophagy
High protein turnover results in damaged fungal proteasomes, which are degraded in yeasts
and presumably also in filamentous fungi by
self-eating autophagy (Waite et al. 2016; Hoeller and Dikic 2016). This is, besides the proteasomal degradation, the second major
eukaryotic degradation system. It is a highly
organized membrane-trafficking pathway,
specialized for long-lived proteins as well as
quality control for large and heterogeneous cellular material including protein aggregates or
organelles. Malfunction of this conserved process is, e.g., associated to neurodegenerative
diseases in humans as well as impairment of
accurate fungal secondary metabolism and differentiation. Autophagy provides nutrients
during stress conditions, starvation, or transition phases of developmental programs (Voigt
and Po ¨ggeler 2013; Popova et al. 2018, Fig. 8.4).
Fungi produce secondary metabolites, which
directly affect autophagy such as the beneficial
rasfonin from Talaromyces, which reduces different cancer cells by inducing autophagy (Xiao
et al. 2014; Sun et al. 2016).
The targeted engulfment of cellular material by membrane invaginations of the vacuole
is termed microautophagy. Macroautophagy
corresponds to the sequestration of bulk cellular material such as damaged organelles or protein aggregates by de novo formed phagophore,
e.g., during yeast starvation (Li et al. 2012;
Reggiori et al. 2012). Cargo proteins are
engulfed during this process by the double
membrane phagophore, which closes to form
the autophagosome. This compartment fuses
with the fungal vacuole at its outer membrane,
while the inner autophagic body is digested by
the hydrolytic vacuolar milieu. Autophagy can
be either non-selective or selective. Selective
autophagy for the degradation of different cellular organelles, e.g., the pexophagy for defective peroxisomes in Sordaria macrospora,
requires specific cargo receptors (Werner et al.
2019).
Instead of degradation, selective autophagy
pathways can also be used for hydrolytic
enzyme transportation to the vacuole as the
yeast cytoplasm-to-vacuole transport (Cvt)
pathway (Lynch-Day and Klionsky 2010). Fungal secondary metabolism takes place in different cellular compartments such as the
cytoplasm, the peroxisomes, vesicles, or
vacuoles. The transport of enzymes and metabolic compounds or precursors is therefore
often mediated through autophagic pathways.
For instance, aflatoxin production requires a
complex interplay of different autophagic processes. Vesicles bud from mitochondria and
peroxisomes, which deliver precursors and
enzymes to Cvt vesicles containing other
enzymes of the biosynthetic pathway to form
the aflatoxisomes. Aflatoxisomes mediate the
biosynthesis by the transport of active enzymes
as well as compartmentalization by storing different aflatoxin intermediates and the aflatoxin
export to the cell exterior (Chanda et al. 2009;
Roze et al. 2011a).
Autophagy-associated atg genes were first
identified in the unicellular fungus S. cerevisiae.
Until 2016, 42 yeast atg genes were identified
including 18 core genes for autophagosome
formation, which are mostly conserved in filamentous fungi (Wen and Klionsky 2016; Parzych et al. 2018).
In the initiation phase, starvation-induced
autophagy requires an active Atg1 Ser/Thr
kinase complex, which is inhibited under nonstarvation conditions by the active Tor (target
of rapamycin) kinase complex, sensing nitro194
J. Gerke et al.