VI. Conclusion
The burden of infectious diseases caused by
bacteria and fungi, which are resistant to the
usual antibiotics or antimycotics such as azoles,
is growing (Cassini et al. 2019; Lestrade et al.
2019). Filamentous fungi form a vast reservoir
of yet unknown beneficial or toxic secondary
metabolites, which are only produced as
responses to environmental biotic or abiotic
stimuli. A more comprehensive picture of the
complex and subtle control of transcriptional
networks, which are nested within each other,
are more and more emerging. They interconnect distinct fungal developmental programs
with the production of specific secondary metabolites. This includes the genetic networks of
the fungal velvet domain proteins and their
sub-networks, which link transcriptional to
epigenetic control of gene expression, but also
protein degradation machineries like the 26S
proteasome and the autophagy membrane trafficking pathway. They control maintenance or
changes of fungal proteomes as well as cellular
localization and transport of proteins as additional levels of coordinating secondary metabolite production in response to environmental
parameters or during development, aging, or
pathogenesis. Manipulation of gene expression
including chemical epigenetics as well as
genetic or chemical reprogramming of fungal
protein degradation are promising approaches
to find new biologically active secondary metabolites acting as antibiotics or as antifungal
drugs.
Acknowledgments We thank Fruzsina Bakti and Christoph Sasse for critical reading of the manuscript. Funding of this research was provided by the Deutsche
Forschungsgemeinschaft (DFG) and the SFB860.
References
Adams TH, Wieser JK, Yu JH (1998) Asexual sporulation in Aspergillus nidulans. Microbiol Mol Biol
Rev 62:35–54
Adhvaryu KK, Morris SA, Strahl BD, Selker EU (2005)
Methylation of histone H3 lysine 36 is required for
normal development in Neurospora crassa. Eukaryot Cell 4:1455–1464
Ahmed YL, Gerke J, Park H-S, Bayram O ¨ , Neumann P,
Ni M, Dickmanns A, Kim SC, Yu J-H, Braus GH,
Ficner R (2013) The velvet family of fungal regulators contains a DNA-binding domain structurally similar to NF-kB. PLoS Biol 11:e1001750
Alberti F, Foster GD, Bailey AM (2017) Natural products from filamentous fungi and production by
heterologous expression. Appl Microbiol Biotechnol 101:493–500
Amerik AY, Li S, Hochstrasser M (2000) Analysis of the
deubiquitinating enzymes of the yeast Saccharomyces cerevisiae. Biol Chem 381:981–992
Andersen MR, Nielsen JB, Klitgaard A, Petersen LM,
Zachariasen M, Hansen TJ, Blicher LH, Gotfredsen
CH, Larsen TO, Nielsen KF, Mortensen UH (2013)
Accurate prediction of secondary metabolite gene
clusters in filamentous fungi. Proc Natl Acad Sci
USA 110:E99–E107
Bachand F (2007) Protein arginine methyltransferases:
from unicellular eukaryotes to humans. Eukaryot
Cell 6:889–898
Bahn Y-S, Xue C, Idnurm A, Rutherford JC, Heitman J,
Cardenas ME (2007) Sensing the environment:
lessons from fungi. Nat Rev Microbiol 5:57–69
Barth E, Hu ¨bler R, Baniahmad A, Marz M (2016) The
evolution of COP9 signalosome in unicellular and
multicellular organisms. Genome Biol Evol
8:1279–1289
Bartoszewska M, Kiel JAKW, Bovenberg RAL, Veenhuis
M, van der Klei IJ (2011) Autophagy deficiency
promotes beta-lactam production in Penicillium
chrysogenum. Appl Environ Microbiol 77:1413–
1422
Bauer I, Graessle S, Loidl P, Hohenstein K, Brosch G
(2010) Novel insights into the functional role of
three protein arginine methyltransferases in Aspergillus nidulans. Fungal Genet Biol 47:551–561
Bauer I, Varadarajan D, Pidroni A, Gross S, Vergeiner
S, Faber B, Hermann M, Tribus M, Brosch G,
Graessle S, Turgeon EBG (2016) A class 1 histone
deacetylase with potential as an antifungal target.
MBio 7:e00831–e00816
Bayram O ¨ , Braus GH (2012) Coordination of secondary
metabolism and development in fungi: the velvet
family of regulatory proteins. FEMS Microbiol Rev
36:1–24
Bayram O, Biesemann C, Krappmann S, Galland P,
Braus GH (2008a) More than a repair enzyme:
Aspergillus nidulans photolyase-like CryA is a regulator of sexual development. Mol Biol Cell
19:3254–3262
Bayram O ¨ , Krappmann S, Ni M, Bok JW, Helmstaedt K,
Valerius O, Braus-Stromeyer S, Kwon NJ, Keller
NP, Yu J, Braus GH (2008b) VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science
320:1504–1506
Bayram O ¨ , Krappmann S, Seiler S, Vogt N, Braus GH
(2008c) Neurospora crassa ve-1 affects asexual
conidiation. Fungal Genet Biol 45:127–138
196
J. Gerke et al.
The burden of infectious diseases caused by
bacteria and fungi, which are resistant to the
usual antibiotics or antimycotics such as azoles,
is growing (Cassini et al. 2019; Lestrade et al.
2019). Filamentous fungi form a vast reservoir
of yet unknown beneficial or toxic secondary
metabolites, which are only produced as
responses to environmental biotic or abiotic
stimuli. A more comprehensive picture of the
complex and subtle control of transcriptional
networks, which are nested within each other,
are more and more emerging. They interconnect distinct fungal developmental programs
with the production of specific secondary metabolites. This includes the genetic networks of
the fungal velvet domain proteins and their
sub-networks, which link transcriptional to
epigenetic control of gene expression, but also
protein degradation machineries like the 26S
proteasome and the autophagy membrane trafficking pathway. They control maintenance or
changes of fungal proteomes as well as cellular
localization and transport of proteins as additional levels of coordinating secondary metabolite production in response to environmental
parameters or during development, aging, or
pathogenesis. Manipulation of gene expression
including chemical epigenetics as well as
genetic or chemical reprogramming of fungal
protein degradation are promising approaches
to find new biologically active secondary metabolites acting as antibiotics or as antifungal
drugs.
Acknowledgments We thank Fruzsina Bakti and Christoph Sasse for critical reading of the manuscript. Funding of this research was provided by the Deutsche
Forschungsgemeinschaft (DFG) and the SFB860.
References
Adams TH, Wieser JK, Yu JH (1998) Asexual sporulation in Aspergillus nidulans. Microbiol Mol Biol
Rev 62:35–54
Adhvaryu KK, Morris SA, Strahl BD, Selker EU (2005)
Methylation of histone H3 lysine 36 is required for
normal development in Neurospora crassa. Eukaryot Cell 4:1455–1464
Ahmed YL, Gerke J, Park H-S, Bayram O ¨ , Neumann P,
Ni M, Dickmanns A, Kim SC, Yu J-H, Braus GH,
Ficner R (2013) The velvet family of fungal regulators contains a DNA-binding domain structurally similar to NF-kB. PLoS Biol 11:e1001750
Alberti F, Foster GD, Bailey AM (2017) Natural products from filamentous fungi and production by
heterologous expression. Appl Microbiol Biotechnol 101:493–500
Amerik AY, Li S, Hochstrasser M (2000) Analysis of the
deubiquitinating enzymes of the yeast Saccharomyces cerevisiae. Biol Chem 381:981–992
Andersen MR, Nielsen JB, Klitgaard A, Petersen LM,
Zachariasen M, Hansen TJ, Blicher LH, Gotfredsen
CH, Larsen TO, Nielsen KF, Mortensen UH (2013)
Accurate prediction of secondary metabolite gene
clusters in filamentous fungi. Proc Natl Acad Sci
USA 110:E99–E107
Bachand F (2007) Protein arginine methyltransferases:
from unicellular eukaryotes to humans. Eukaryot
Cell 6:889–898
Bahn Y-S, Xue C, Idnurm A, Rutherford JC, Heitman J,
Cardenas ME (2007) Sensing the environment:
lessons from fungi. Nat Rev Microbiol 5:57–69
Barth E, Hu ¨bler R, Baniahmad A, Marz M (2016) The
evolution of COP9 signalosome in unicellular and
multicellular organisms. Genome Biol Evol
8:1279–1289
Bartoszewska M, Kiel JAKW, Bovenberg RAL, Veenhuis
M, van der Klei IJ (2011) Autophagy deficiency
promotes beta-lactam production in Penicillium
chrysogenum. Appl Environ Microbiol 77:1413–
1422
Bauer I, Graessle S, Loidl P, Hohenstein K, Brosch G
(2010) Novel insights into the functional role of
three protein arginine methyltransferases in Aspergillus nidulans. Fungal Genet Biol 47:551–561
Bauer I, Varadarajan D, Pidroni A, Gross S, Vergeiner
S, Faber B, Hermann M, Tribus M, Brosch G,
Graessle S, Turgeon EBG (2016) A class 1 histone
deacetylase with potential as an antifungal target.
MBio 7:e00831–e00816
Bayram O ¨ , Braus GH (2012) Coordination of secondary
metabolism and development in fungi: the velvet
family of regulatory proteins. FEMS Microbiol Rev
36:1–24
Bayram O, Biesemann C, Krappmann S, Galland P,
Braus GH (2008a) More than a repair enzyme:
Aspergillus nidulans photolyase-like CryA is a regulator of sexual development. Mol Biol Cell
19:3254–3262
Bayram O ¨ , Krappmann S, Ni M, Bok JW, Helmstaedt K,
Valerius O, Braus-Stromeyer S, Kwon NJ, Keller
NP, Yu J, Braus GH (2008b) VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science
320:1504–1506
Bayram O ¨ , Krappmann S, Seiler S, Vogt N, Braus GH
(2008c) Neurospora crassa ve-1 affects asexual
conidiation. Fungal Genet Biol 45:127–138
196
J. Gerke et al.