Download Endoplasmic reticulum(ER)

Glucose-regulated proteins in the ER Stress and Oxidative Stress response
Structural Biology Lab
Chang Woo Han
Contents
• Endoplasmic reticulum(ER)
• Mitochondria
• Cross-talk between ER Stress and Oxidative Stress
• Cancer
• Targeting GRPs
• Conclusions
Endoplasmic reticulum(ER)
•Function
①Protein Folding
②Lipid biosynthesis
③Calcium storage and release
https://global.britannica.com/science/endoplasmic-reticulum
Endoplasmic reticulum(ER)
①
②,③
SRP: signal recognition particle
SR: SR receptor
PDI: protein disulfide isomerase
ERp57: protein disulfide-isomerase A3(PDIA3)
CNX: calnexin
CRT: calreticulin
Ageing Res Rev. 2009 Jul;8(3):150-9.
•Protein folding and quality control
①First, Sec61p translocon complex: Co-translational and Co-translocational folding(Nascent protein)
②Second, Ribosome: Post-translational folding(Poly-peptide)
③Finally, Chaperones and Folding enzymes: oligomeric assembly(Protein)
Endoplasmic reticulum(ER)
• Perturbations of ER homeostasis → unfolded protein and protein aggregate
• Accumulation of unfolded proteins and misfolded proteins→ ER stress
① including ER
Ca2 +
④redox state
② glycosylation
⑤metabolic and
inflammatory
challenges
③ energy stores
⑥increased ERassociated mRNA
translation
⑦expression of
proteins that are
prone to misfolding
Unfolded protein response(URP)
• The UPR enhances the ER capacity for protein folding and modification, attenuates global
mRNA translation, and disposes terminally misfolded proteins by ER-associated protein
degradation (ERAD) and autophagy.
Endoplasmic reticulum(ER)
•Unfolded protein response(ER stress response)
Glucose-regulated proteins(GRPs): Unfolded protein response signalling regulator ex)GRP78(Bip)
③
Bip: glucose-regulated
proteins 78
IRE1: inositol-requiring
kinase 1
eIF2α: eukaryotic
translation initiation
factor 2
PERK: pancreatic ER
eukaryotic translation
initiation factor 2(eIF2α)
kinase
ATF6: activating
transcription factor 6
NRF2: nuclear factor
(erythroid-derived 2)like 2
ERAD: ER-associated
protein degradation
②
①
Ageing Res Rev. 2009 Jul;8(3):150-9.
Endoplasmic reticulum(ER)
Redox changes and Reactive Oxygen Species(ROS)
GSH: glutathione
GSSG: glutathione disulfide
PDI: protein disulfide isomerase
Ero1: ER oxidoreductin 1
Antioxid Redox Signal. 2014 Jul 20;21(3):396-413.
Mitochondria
TCA cycle and Electron transport chain
Int J Mol Sci. 2014 Dec 5;15(12):22604-25.
Cross-talk between ER Stress and Oxidative Stress
Oxidative
Stress
Antioxid Redox Signal. 2014 Jul 20;21(3):396-413.
Cross-talk between ER Stress and Oxidative Stress
Glutathione peroxidase (NPGPx) : NPGPx Serves as a Sensor for ER Oxidative Stress
Mol Cell. 2012 Dec 14;48(5):747-59.
•Oxidized NPGPx Interacts with GRP78 to Form a Disulfide-Linked Complex.
: NPGPx Positively Modulates GRP78 Chaperone Activity to Relieve ER Oxidative Stress.
Cancer
ROS play multiple roles in the hallmarks of cancers.
Int J Cell Biol. 2012;2012:762825.
Cancer
Comparison of Glycolysis between a Normal Tissue and Tumour/ Proliferated Tissue
Science. 2009 May 22;324(5930):1029-33.
▪ ~10% Biosynthetic pathway
①Pentose phosphate pathway(PPP), ②Amino acid synthesis, ③Nucleotide synthesis, ④NADPH
biosynthesis
Cancer
Both stresses activate angiogenesis.
HIF1α; hypoxia-inducible factor
VEGF: Vascular endothelial growth
factor
VEGFR 2: VEGF receptor 2
TLR: Toll-like receptor
p50-p65 heterodimer: NF-kB
Mol Cancer. 2015 Nov 19;14:198.
Cancer
HIF-1, an essential transcription factor during the hypoxic response, is regulated by both
ER stress and oxidative stress.
PHDs: prolyl hydroxylases
Front Aging Neurosci. 2010; 2: 138.
Cancer
Hypoxia activates the unfolded protein response.
XBP1: X-box-binding protein 1
ATF6: activating transcription factor 4
mTOR: mammalian target of rapamycin
Nat Rev Cancer. 2008 Nov;8(11):851-64.
Cancer
HIF-1 causes induction of c-Myc, which improve cancer cell survival through
PERK/eIF2a/ATF4-dependent induction of autophagy.
C-Myc:
Nat Rev Cancer. 2008 Nov;8(11):851-64.
Targeting GRPs
Association of elevated GRP protein level in patient samples with cancer aggressiveness
and poor survival
https://global.britannica.com/science/endoplasmic-reticulum
Targeting GRPs
GRPs in survival and immunity
https://global.britannica.com/science/endoplasmic-reticulum
Targeting GRPs
Role of GRP78 and GRP94 in mouse models of cancer
https://global.britannica.com/science/endoplasmic-reticulum
Conclusions
• ER stress and Oxidative stress are highly inter-related biological processes
• The two stresses coexist and induce each other, but also reflected by the multifunctional stress responses which target both ER protein misfolding and redox
imbalance.
• The two cellular stresses profoundly impact normal physiology as well as many
human cancers.
• Recently, studies suggest that the two stresses and their downstream signaling
pathways are promising targets for novel therapeutics.
Thank you