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Engineering of chaperone systems and of the unfolded protein response

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Abstract

Production of recombinant proteins in mammalian cells is a successful technology that delivers protein pharmaceuticals for therapies and for diagnosis of human disorders. Cost effective production of protein biopharmaceuticals requires extensive optimization through cell and fermentation process engineering at the upstream and chemical engineering of purification processes at the downstream side of the production process. The majority of protein pharmaceuticals are secreted proteins. Accumulating evidence suggests that the folding and processing of these proteins in the endoplasmic reticulum (ER) is a general rate- and yield limiting step for their production. We will summarize our knowledge of protein folding in the ER and of signal transduction pathways activated by accumulation of unfolded proteins in the ER, collectively called the unfolded protein response (UPR). On the basis of this knowledge we will evaluate engineering approaches to increase cell specific productivities through engineering of the ER-resident protein folding machinery and of the UPR.

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Abbreviations

4E-BP1:

4E-Binding protein 1

ADP:

Adenosine diphosphate

AKT:

AKR/J Mice transforming retroviral oncogene

AP-1:

Activation protein 1

ASK1:

Apoptosis signal-regulating kinase 1

Asn:

L-Asparagine

ATF4:

Activating transcription factor 4

ATF5:

Activating transcription factor 5

ATF6α:

Activating transcription factor 6α

ATF6β:

Activating transcription factor 6β

ATG5:

Autophagy-related 5

Atg8p:

Autophagy-related 8 protein

ATG12:

Autophagy-related 12

ATG16:

Autophagy-related 16

ATP:

Adenosine triphosphate

BAK:

BCL-2 Homologous antagonist/killer

BAP:

BiP-Associated protein

BAX:

BCL-2-Associated X protein

BBF2:

Box B-binding factor 2

BCL-2:

B Cell leukemia/lymphoma 2

BH1:

BCL-2 Homology domain 1

BH2:

BCL-2 Homology domain 2

BH3:

BCL-2 Homology domain 3

BH4:

BCL-2 Homology domain 4

BIM:

BCL-2 Interacting mediator of cell death

BiP:

Heavy chain binding protein

BMF:

BCL-2 Modifying factor

bZIP:

Basic leucine zipper

cAMP:

Cyclic adenosine monophosphate

CD154:

Cluster of differentiation 154

Cdc48p:

Cell division cycle 48 protein

CDP:

Cytidine diphosphate

CHO:

Chinese hamster ovary

CHOP:

CCAAT/Enhancer-binding protein (C/EBP) homologous protein

cIAP1:

Cellular inhibitor of apoptosis 1

CNC:

Cap and collar

CoA:

Coenzyme A

COPII:

Coat Protein II

CRE:

cAMP Response element

CREB3:

CRE-Binding protein 3

CREB4:

CRE-Binding protein 4

CREB-H:

CREB Homolog

Cue1p:

Coupling of ubiquitin conjugation to ER degradation 1 protein

DD:

Death domain

DED:

Death effector domain

DnaJ:

2′-Deoxyribonucleic acid chain elongation J

DR3:

Death receptor 3

DR6:

Death receptor 6

DTT:

1,4-DL-Dithiothreitol

E 1 :

Ubiquitin-activating enzyme

E 2 :

Factor eluted by DTT (ubiquitin-conjugating enzyme)

E 3 :

Eluted with high salt or high pH (ubiquitin ligase)

ECH:

Erythroid cell-derived protein with CNC homology

EDEM1:

ER Degradation enhancer, mannosidase α-like 1

EDEM2:

ER Degradation enhancer, mannosidase α-like 2

EDEM3:

ER Degradation enhancer, mannosidase α-like 3

eIF2α:

Eukaryotic translation initiation factor 2α

eIF2B:

Eukaryotic translation initiation factor 2B

EIF2AK3:

eIF2α Kinase 3

eIF-4E:

Eukaryotic translation initiation factor 4E

ER:

Endoplasmic reticulum

ERAD:

ER Associated protein degradation

ERdj1:

ER DnaJ Protein 1

ERdj2:

ER DnaJ Protein 2

ERdj3:

ER DnaJ Protein 3

ERdj4:

ER DnaJ Protein 4

ERdj5:

ER DnaJ Protein 5

ERGIC-53:

ER Golgi intermediate compartment protein of 53 kDa

ERK1:

Extracellular signal regulated kinase 1

ERK2:

Extracellular signal regulated kinase 2

ERO1-Lα:

Ero1p-like α

ERO1-Lβ:

Ero1p-like β

Ero1p:

ER Oxidation 1 protein

ERp57:

ER Protein of 57 kDa

ERSE-I:

ER Stress response element I

ERSE-II:

ER Stress response element II

Erv2p:

Essential for respiration and viability 2 protein

FAD:

Flavine adenine dinucleotide

FADD:

FAS-Associated protein with a novel DD

GADD34:

Growth arrest and DNA damage gene 34

GADD45β:

Growth arrest and DNA damage gene 45β

Glc:

d-Glucose

α-Glc I:

α-Glucosidase I

α-Glc II:

α-Glucosidase II

GlcNAC:

2-N-Acetyl-d-glucosamine

GRP78:

Glucose-regulated protein of 78 kDa

GRP94:

Glucose-regulated protein of 94 kDa

GRP170:

Glucose-regulated protein of 170 kDa

GrpE:

Growth after phage induction E

Hac1p:

Homologous to ATF/CREB1 1 protein

HEDJ:

Human ER-associated DnaJ

HERP:

Hyperhomocysteinemia-induced ER stress-responsive protein

hIAP2:

Human inhibitor of apoptosis 2

HMG:

3-Hydroxy-3-methylglutarate

Hrd1p:

HMG-CoA reductase degradation 1 protein

Hrd3p:

HMG-CoA Reductase degradation 3 protein

HSP40:

Heat shock protein of 40 kDa

HSP70:

Heat shock protein of 70 kDa

HSP90:

Heat shock protein of 90 kDa

IAP:

Inhibitor of apoptosis

IgG:

Immunoglobulin G

IκB:

Inhibitor of NF-κB

IKK:

IκB Kinase

IL-2:

Interleukin 2

IL-6:

Interleukin 6

IL-8:

Interleukin 8

IRE1α:

Inositol requiring 1α

IRE1β:

Inositol requiring 1β

IRS-1:

Insulin receptor substrate 1

IRS-2:

Insulin receptor substrate 2

JNK:

JUN N-Terminal kinase

JUN:

Ju-nana

KEAP1:

Kelch-like ECH-associated protein 1

LC3:

Microtubule-associated protein 1 light chain 3

LDLR:

Low density lipoprotein receptor

Lhs1p:

Luminal HSP70 1 protein

m7G:

7-Methylguanosine

Man:

D-Mannose

MAP:

Mitogen-activated protein

MAPKKK:

MAP Kinase kinase kinase

MCP-1:

Monocyte chemoattractant protein 1

MDG1:

Microvascular differentiation gene 1

MEF:

Mouse embryonic fibroblast

MKK7:

Mitogen-activated protein kinase kinase 7

mRNA:

Messenger RNA

mTNF:

Membrane-bound TNF

MTJ1:

Murine tumor cell DnaJ-like protein 1

mTOR:

Mammalian TOR

NADPH:

Reduced nicotine adenine dinucleotide phosphate

NF-κB:

Nuclear factor κB

NOXA:

NADPH Oxidase activator

NRF2:

Nuclear factor erythroid 2-related factor 2

NS0:

Non-secreting myeloma cell

OASIS:

Old astrocyte specifically induced substance

ORP150:

150 kDa Oxygen-regulated protein

p38:

Protein of 38 kDa

p58IPK :

58 kDa Inhibitor of PKR

p65:

65 kDa Protein

p70S6K :

70,000 M r 40 S Ribosomal protein S6 kinase

p97:

Protein of 97 kDa

PDI:

Protein disulfide isomerase

PDK:

Phosphoinositide-dependent kinase 2

PEK:

Pancreatic eIF2α kinase

PERK:

PKR-Like ER kinase

Pi :

Inorganic phosphate (HPO4 2−)

PI:

Phosphatidylinositol

PI3K:

PI 3-Kinase

PKB:

Protein kinase B

PKR:

Double-stranded RNA-activated protein kinase

PP1:

Protein phosphatase 1

PPi :

Pyrophosphate (HP2O7 3−)

PPI:

Cis–trans peptidyl prolyl isomerase

pQC:

Preemptive quality control

PUMA:

p53 Upregulated modulator of apoptosis

Q6:

Quiescin 6

QSCN6:

Quiescin 6

QSCN6L1:

Quiescin 6-like 1

QSOX1:

Quiescin Q6 sulfhydryl oxidase 1

QSOX2:

Quiescin Q6 sulfhydryl oxidase 2

RAS:

Rat sarcoma

RIP:

Receptor interacting protein

RNA:

Ribonucleic acid

RNAi:

RNA Interference

ROS:

Reactive oxygen species

rRNA:

Ribosomal RNA

S1P:

Site 1 protease

S2P:

Site 2 protease

SEC61:

Secretory 61

SEC63:

Secretory 63

Ser:

l-Serine

SERCA:

Sarcoplasmic or endoplasmic reticulum Ca2+ ATPase

SH-2:

Src Homology 2 domain

SHC:

SH-2 Domain containing

SIL1:

Suppressor of IRE1/LHS1 synthetic lethality 1

SODD:

Silencer of death domains

SOXN:

Neuroblastoma-derived sulfhydryl oxidase

Src:

Sarcoma formation

SRE:

Sterol response element

sTNF:

Soluble TNF

TACE:

TNF-α Converting enzyme

Thr:

l-Threonine

TIM:

TRAF-Interacting motif

TNF-α:

Tumor necrosis factor α

TNF-R:

TNF-α receptor

TOR:

Target of rapamycin

TRADD:

TNF-R-Associated via DD

TRAF2:

TNF-R Associated factor 2

TRAIL-R1:

TNF-Related apoptosis-inducing ligand receptor 1

TRAIL-R2:

TNF-Related apoptosis-inducing ligand receptor 2

TRB3:

Tribbles homolog 3

tRNA:

Transfer RNA

TSC1:

Tuberous sclerosis complex 1

TSC2:

Tuberous sclerosis complex 2

Ub:

Ubiquitin

Ubc7p:

Ubiquitin-conjugating enzyme 7 protein

UDP:

Uridine diphosphate

UGGT:

UDP-Glucose:glycoprotein glucosyltransferase

UPR:

Unfolded protein response

VCP:

Valosin-containing protein

WT:

Wild type

XBP-1:

X-Box-binding protein 1

Yos9p:

Yeast osteosarcoma 9 homolog protein

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Acknowledgements

We apologize to all whose work could not be cited because of space limitations. This work was supported by funding from the Biotechnology and Biological Sciences Research Council (C513418/1, D01588X/1, E006035/1), the European Commission (HEALTH-F7-2007-201608), and the Wellcome Trust (079821) to M.S.

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    Saeed U. Khan & Martin Schröder

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Khan, S.U., Schröder, M. Engineering of chaperone systems and of the unfolded protein response. Cytotechnology 57, 207–231 (2008). https://doi.org/10.1007/s10616-008-9157-9

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  • DOI: https://doi.org/10.1007/s10616-008-9157-9

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