Protein production in filamentous fungi

cellular responses and strain improvement

Research output: Chapter in Book/Report/Conference proceedingConference abstract in proceedingsScientific

Abstract

In recent years our understanding of cellular responses in Trichoderma and Aspergillus towards secretion load has increased significantly. Production of large amounts of native proteins or production of difficult foreign proteins provokes secretion stress that is believed in particular to be caused by folding limitations within the ER. Impairnment of folding causes the so called unfolded protein response (UPR), which is mediated by the regulatory protein HAC that causes modification of expression of a number of genes involved in various cellular processes related to protein secretion. In addition to the classical UPR, also other cell responses have been discovered using genome-wide approaches. Furthermore, a novel mechanism (RESS) has been identified that down-regulates expression of genes encoding native secreted proteins such as cellulases and glycoamylase under secretion stress conditions. These results show that the function of the secretory pathway is interlinked with other cellular processes, and that several feed-back mechanisms may exist that serve to balance between expression, folding, glycosylation and secretion of proteins. It is possible to alter these cellular mechanisms and create improved production strains. For instance, overexpression of HACA increases production of calf chymosin and laccase in A.niger. The EC-funded Eurofung consortium has studied protein secretion in filamentous fungi and some of the results obtained will also be presented. References: Pakula, T.M., Laxell, M., Huuskonen, A., Uusitalo, J., Saloheimo, M. & Penttilä, M. 2003. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J. Biol. Chem. 278, 45011-45020. Saloheimo, M., Valkonen, M. & Penttilä, M. 2003. Activation mechanisms of the HACI-mediated unfolded protein response in filamentous fungi. Mol. Microbiol. 47, 1149 1161. Valkonen, M., Penttilä, M. & Saloheimo, M. 2003. Effects of inactivation and constitutive expression of the unfolded-protein response pathway on protein production in the yeast Saccharomyces cerevisiae. Appl. Env. Microb. 69, 2065-2072. Valkonen, M., Ward, M., Wang, H., Penttilä, M. & Saloheimo, M. 2003. Improvement of foreign-protein production in Aspergillus niger var. awamori by constitutive induction of the unfolded-protein response. Appl. Env. Microb. 69, 6979-6986. Mulder, H. J., Saloheimo, M., Penttilä, M. & Madrid, S.M. The transcription factor HACA mediates the unfolded protein response in Aspergillus niger, and upregulates the transcription of its own gene. Mol. Gen. Genet., in press.
Original languageEnglish
Title of host publicationPlenary Lecture Abstracst
Pages43
Publication statusPublished - 2004
Event7th European Conference on Fungal Genetics - Copenhagen, Denmark
Duration: 17 Apr 200420 Apr 2004

Conference

Conference7th European Conference on Fungal Genetics
CountryDenmark
CityCopenhagen
Period17/04/0420/04/04

Fingerprint

unfolded protein response
protein secretion
fungi
proteins
Aspergillus niger
secretion
chymosin
Trichoderma reesei
cellulases
genes
laccase
regulatory proteins
Trichoderma
glycosylation
Aspergillus
Saccharomyces cerevisiae
inactivation
transcription factors
transcription (genetics)
calves

Cite this

@inbook{a4cbda2daa3344499850d44538a5c8e0,
title = "Protein production in filamentous fungi: cellular responses and strain improvement",
abstract = "In recent years our understanding of cellular responses in Trichoderma and Aspergillus towards secretion load has increased significantly. Production of large amounts of native proteins or production of difficult foreign proteins provokes secretion stress that is believed in particular to be caused by folding limitations within the ER. Impairnment of folding causes the so called unfolded protein response (UPR), which is mediated by the regulatory protein HAC that causes modification of expression of a number of genes involved in various cellular processes related to protein secretion. In addition to the classical UPR, also other cell responses have been discovered using genome-wide approaches. Furthermore, a novel mechanism (RESS) has been identified that down-regulates expression of genes encoding native secreted proteins such as cellulases and glycoamylase under secretion stress conditions. These results show that the function of the secretory pathway is interlinked with other cellular processes, and that several feed-back mechanisms may exist that serve to balance between expression, folding, glycosylation and secretion of proteins. It is possible to alter these cellular mechanisms and create improved production strains. For instance, overexpression of HACA increases production of calf chymosin and laccase in A.niger. The EC-funded Eurofung consortium has studied protein secretion in filamentous fungi and some of the results obtained will also be presented. References: Pakula, T.M., Laxell, M., Huuskonen, A., Uusitalo, J., Saloheimo, M. & Penttil{\"a}, M. 2003. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J. Biol. Chem. 278, 45011-45020. Saloheimo, M., Valkonen, M. & Penttil{\"a}, M. 2003. Activation mechanisms of the HACI-mediated unfolded protein response in filamentous fungi. Mol. Microbiol. 47, 1149 1161. Valkonen, M., Penttil{\"a}, M. & Saloheimo, M. 2003. Effects of inactivation and constitutive expression of the unfolded-protein response pathway on protein production in the yeast Saccharomyces cerevisiae. Appl. Env. Microb. 69, 2065-2072. Valkonen, M., Ward, M., Wang, H., Penttil{\"a}, M. & Saloheimo, M. 2003. Improvement of foreign-protein production in Aspergillus niger var. awamori by constitutive induction of the unfolded-protein response. Appl. Env. Microb. 69, 6979-6986. Mulder, H. J., Saloheimo, M., Penttil{\"a}, M. & Madrid, S.M. The transcription factor HACA mediates the unfolded protein response in Aspergillus niger, and upregulates the transcription of its own gene. Mol. Gen. Genet., in press.",
author = "Merja Penttil{\"a} and Mikko Arvas and Tiina Pakula and Jari Rautio and Mari Valkonen and Markku Saloheimo",
year = "2004",
language = "English",
pages = "43",
booktitle = "Plenary Lecture Abstracst",

}

Penttilä, M, Arvas, M, Pakula, T, Rautio, J, Valkonen, M & Saloheimo, M 2004, Protein production in filamentous fungi: cellular responses and strain improvement. in Plenary Lecture Abstracst., L-7, pp. 43, 7th European Conference on Fungal Genetics, Copenhagen, Denmark, 17/04/04.

Protein production in filamentous fungi : cellular responses and strain improvement. / Penttilä, Merja; Arvas, Mikko; Pakula, Tiina; Rautio, Jari; Valkonen, Mari; Saloheimo, Markku.

Plenary Lecture Abstracst. 2004. p. 43 L-7.

Research output: Chapter in Book/Report/Conference proceedingConference abstract in proceedingsScientific

TY - CHAP

T1 - Protein production in filamentous fungi

T2 - cellular responses and strain improvement

AU - Penttilä, Merja

AU - Arvas, Mikko

AU - Pakula, Tiina

AU - Rautio, Jari

AU - Valkonen, Mari

AU - Saloheimo, Markku

PY - 2004

Y1 - 2004

N2 - In recent years our understanding of cellular responses in Trichoderma and Aspergillus towards secretion load has increased significantly. Production of large amounts of native proteins or production of difficult foreign proteins provokes secretion stress that is believed in particular to be caused by folding limitations within the ER. Impairnment of folding causes the so called unfolded protein response (UPR), which is mediated by the regulatory protein HAC that causes modification of expression of a number of genes involved in various cellular processes related to protein secretion. In addition to the classical UPR, also other cell responses have been discovered using genome-wide approaches. Furthermore, a novel mechanism (RESS) has been identified that down-regulates expression of genes encoding native secreted proteins such as cellulases and glycoamylase under secretion stress conditions. These results show that the function of the secretory pathway is interlinked with other cellular processes, and that several feed-back mechanisms may exist that serve to balance between expression, folding, glycosylation and secretion of proteins. It is possible to alter these cellular mechanisms and create improved production strains. For instance, overexpression of HACA increases production of calf chymosin and laccase in A.niger. The EC-funded Eurofung consortium has studied protein secretion in filamentous fungi and some of the results obtained will also be presented. References: Pakula, T.M., Laxell, M., Huuskonen, A., Uusitalo, J., Saloheimo, M. & Penttilä, M. 2003. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J. Biol. Chem. 278, 45011-45020. Saloheimo, M., Valkonen, M. & Penttilä, M. 2003. Activation mechanisms of the HACI-mediated unfolded protein response in filamentous fungi. Mol. Microbiol. 47, 1149 1161. Valkonen, M., Penttilä, M. & Saloheimo, M. 2003. Effects of inactivation and constitutive expression of the unfolded-protein response pathway on protein production in the yeast Saccharomyces cerevisiae. Appl. Env. Microb. 69, 2065-2072. Valkonen, M., Ward, M., Wang, H., Penttilä, M. & Saloheimo, M. 2003. Improvement of foreign-protein production in Aspergillus niger var. awamori by constitutive induction of the unfolded-protein response. Appl. Env. Microb. 69, 6979-6986. Mulder, H. J., Saloheimo, M., Penttilä, M. & Madrid, S.M. The transcription factor HACA mediates the unfolded protein response in Aspergillus niger, and upregulates the transcription of its own gene. Mol. Gen. Genet., in press.

AB - In recent years our understanding of cellular responses in Trichoderma and Aspergillus towards secretion load has increased significantly. Production of large amounts of native proteins or production of difficult foreign proteins provokes secretion stress that is believed in particular to be caused by folding limitations within the ER. Impairnment of folding causes the so called unfolded protein response (UPR), which is mediated by the regulatory protein HAC that causes modification of expression of a number of genes involved in various cellular processes related to protein secretion. In addition to the classical UPR, also other cell responses have been discovered using genome-wide approaches. Furthermore, a novel mechanism (RESS) has been identified that down-regulates expression of genes encoding native secreted proteins such as cellulases and glycoamylase under secretion stress conditions. These results show that the function of the secretory pathway is interlinked with other cellular processes, and that several feed-back mechanisms may exist that serve to balance between expression, folding, glycosylation and secretion of proteins. It is possible to alter these cellular mechanisms and create improved production strains. For instance, overexpression of HACA increases production of calf chymosin and laccase in A.niger. The EC-funded Eurofung consortium has studied protein secretion in filamentous fungi and some of the results obtained will also be presented. References: Pakula, T.M., Laxell, M., Huuskonen, A., Uusitalo, J., Saloheimo, M. & Penttilä, M. 2003. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J. Biol. Chem. 278, 45011-45020. Saloheimo, M., Valkonen, M. & Penttilä, M. 2003. Activation mechanisms of the HACI-mediated unfolded protein response in filamentous fungi. Mol. Microbiol. 47, 1149 1161. Valkonen, M., Penttilä, M. & Saloheimo, M. 2003. Effects of inactivation and constitutive expression of the unfolded-protein response pathway on protein production in the yeast Saccharomyces cerevisiae. Appl. Env. Microb. 69, 2065-2072. Valkonen, M., Ward, M., Wang, H., Penttilä, M. & Saloheimo, M. 2003. Improvement of foreign-protein production in Aspergillus niger var. awamori by constitutive induction of the unfolded-protein response. Appl. Env. Microb. 69, 6979-6986. Mulder, H. J., Saloheimo, M., Penttilä, M. & Madrid, S.M. The transcription factor HACA mediates the unfolded protein response in Aspergillus niger, and upregulates the transcription of its own gene. Mol. Gen. Genet., in press.

M3 - Conference abstract in proceedings

SP - 43

BT - Plenary Lecture Abstracst

ER -