Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence
Abstract
:1. Introduction
2. An Overview of Cellular Senescence
3. Molecular Mechanism of Integrated Stress Response
4. Distinct Outcomes of ISR
5. ISR in Cellular Metabolism
5.1. ISR and Autophagy
5.2. ISR and Mitochondrial Homeostasis
5.3. ISR and Mitochondrial Unfolded Protein Response
6. Interrelationship between ISR and Cellular Senescence
7. Role of ATF4-Interacting Partners in Cellular Senescence
7.1. ATF4-C/EBP Complex
7.2. ATF4-CHOP(DDIT3) Complex
7.3. ATF4-NRF2 (NFE2L2) Complex
7.4. ATF4 and Other bZIP Transcription Factors
7.5. ATF4 and TRIB3
8. Modulators of ISR and Their Impact on Senescence-Related Conditions
8.1. Inhibitors of ISR
8.2. Activators of ISR
9. Take Home Message
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Abbreviations | |||
ASCs | adipose tissue stem cells | ATF | activating transcription factor |
ATG | autophagy-related | DS | developmental senescence |
hAMSCs | human amniotic mesenchymal stem cells | HCCs | hepatocellular carcinoma cells |
HUVECs | human umbilical vein endothelial cells | IL | interleukin |
ISR | integrated stress response | MAPK | mitogen associated protein kinase |
mTORC1 | mechanistic target of rapamycin | NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
OIS | oncogene-induced senescence | OSIS | oxidative stress-induced senescence |
PIC | preinitiation complex | ROS | reactive oxygen species |
SAHF | senescence associated heterochromatin foci | SASP | senescence-associated secretory phenotype |
T2DM | type 2 diabetes mellitus | TIS | therapy-induced senescence |
uORF | upstream open reading frame | UPRmt | mitochondrial unfolded protein response |
General Abbreviations | Description | Gene ID (Gene Cards) | Gene Description |
AMPK | 5′AMP-activated protein kinase | PRKAA1 | Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 |
ANGPTL4 | angiopoietin like 4 | ANGPTL4 | Hepatic Angiopoietin-Related Protein |
ASNS | asparagine synthetase | ASNS | Asparagine Synthetase (Glutamine-Hydrolyzing) |
BECN1 | beclin 1 | BECN1 | Beclin 1, autophagy-related protein |
BIM | Bcl-2 interacting mediator | BCL2L11 | BCL2 Like 11 |
CDKN2A | cyclin dependent kinase inhibitor 2A | CDKN2A | Cyclin Dependent Kinase Inhibitor 2A |
CEBPA | CEBPB, CCAAT/enhancer-binding protein alpha/beta | CEBPA | CCAAT/Enhancer-Binding Protein Alpha |
cGAS | cyclic GMP-AMP synthase | CGAS | CGAMP Synthase |
CHOP | C/EBP homologous protein | DDIT3 | DNA Damage Inducible Transcript 3 |
CReP | constitutive repressor of eIF2α phosphorylation | PPP1R15B | Protein Phosphatase 1 Regulatory Subunit 15B |
DELE1 | DAP3 binding cell death enhancer 1 | DELE1 | DAP3 Binding Cell Death Enhancer 1 |
DR4 | death receptor 4 | TNFRSF10A | TNF Receptor Superfamily Member 10a |
eIF2α | eukaryotic translation initiation factor subunit alpha | EIF2S1 | Eukaryotic Translation Initiation Factor 2 Subunit Alpha |
EPRS | glutamyl-prolyl-tRNA synthetase | EPRS1 | Glutamyl-Prolyl-TRNA Synthetase 1 |
FRA1 | Fos-related antigen 1 | FOSL1 | FOS Like 1, AP-1 Transcription Factor Subunit |
GABARAP | Gamma-aminobutyric acid receptor-associated protein | GABARAP | Gamma-Aminobutyric Acid Receptor-Associated Protein |
GADD34 | growth arrest and DNA damage-inducible protein 34 | PPP1R15A | Protein Phosphatase 1 Regulatory Subunit 15A |
GCN2 | general control nonderepressible 2 | EIF2AK4 | Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 |
GDF15 | growth differentiation factor 15 | GDF15 | Growth Differentiation Factor 15 |
HRI | heme-regulated eIFα kinase | EIF2AK1 | Eukaryotic Translation Initiation Factor 2 Alpha Kinase 1 |
IKK | IkB kinase | IKBKB | Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Beta |
IRF3 | Interferon regulatory factor 3 | IRF3 | Interferon Regulatory Factor 3 |
JAK1 | Janus kinase 1 | JAK1 | Janus kinase 1 |
JDP2 | Jun dimerization protein 2 | JDP2 | Jun Dimerization Protein 2 |
JNK | c-Jun N-terminal kinase | MAPK8 | Mitogen-Activated Protein Kinase 8 |
KDM6B | lysin demethylase 6B | KDM6B | Lysine Demethylase 6B |
KEAP1 | Kelch-like ECH-associated protein 1 | KEAP1 | Kelch Like ECH Associated Protein 1 |
MAP1LC3B | microtubule-associated protein 1 light chain 3B | MAP1LC3B | Microtubule Associated Protein 1 Light Chain 3 Beta |
MCL1 | myeloid cell leukemia 1 | MCL1 | MCL1 Apoptosis Regulator, BCL2 Family Member |
MDM2 | mouse double minute 2 homolog | MDM2 | MDM2, E3-ubiquitin protein ligase |
mTORC1 | mechanistic target of rapamycin | MTOR | Mechanistic Target Of Rapamycin Kinase |
NBR1 | neihbor of BRCA1 gene 1 | NBR1 | NBR1 Autophagy Cargo Receptor |
NFE2 | nuclear factor erythroid 2-related factor 2 | NFE2 | Nuclear Factor, Erythroid 2 |
Nrf2 | nuclear factor erythroid 2-related factor 2 | NFE2L2 | NFE2 Like BZIP Transcription Factor 2 |
OMA1 | metalloendopeptidase | OMA1 | OMA1 Zinc Metallopeptidase |
PAI-1 | plasminogen activator inhibitor type 1 | SERPINE1 | Serpin Family E Member 1 |
PERK | protein kinase RNA-like ER kinase eIF2α kinase 3 | EIF2AK3 | Eukaryotic Translation Initiation Factor 2 Alpha Kinase 3 |
PKR | protein kinase | EIF2AK2 | Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2 |
PP1 | Protein Phosphatase 1 | PPP1CA | Protein Phosphatase 1 Catalytic Subunit Alpha |
PSPH | phosphoserine phosphatase | PSPH | Phosphoserine Phosphatase |
PUMA | p53 upregulated modulator of apoptosis | BBC3 | BCL2 Binding Component 3 |
RAS | small GTPase | KRAS | KRAS Proto-Oncogene, GTPase |
RIPK1 | Receptor-interacting serine/threonine-protein kinase 1 | RIPK1 | Receptor Interacting Serine/Threonine Kinase 1 |
SA-βGal | senescence-associated beta-galactosidase | GLB1 | Galactosidase Beta 1 |
SQSTM1 | sequestosome 1 | SQSTM1 | Sequestosome 1 |
STING | stimulator of interferon genes | STING1 | Stimulator Of Interferon Response CGAMP Interactor 1 |
TRAIL | tumor necrosis factor-related apoptosis-inducing ligand | TNFSF10 | TNF Superfamily Member 10 |
TRIB3 | tribbles preudokinase 3 | TRIB3 | Tribbles Pseudokinase 3 |
TSC2 | tuberous sclerosis complex 2 protein | TSC2 | TSC Complex Subunit 2 |
ULK1/2 | Unc-51-like autophagy-activating kinase | ULK1 | Unc-51 Like Autophagy Activating Kinase 1 |
VEGFA | vascular endothelial factor A | VEGFA | Vascular Endothelial Growth Factor A |
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Transcription Factor | Interacting Partner | Effect on Senescence | References |
---|---|---|---|
ATF4 | CEBPA, CEBPG | Senescence alleviation through regulation of CARE-containing genes | Horiguchi, M. et al. (2012) [158]; Huggins, C.J. et al. (2016) [159]; Huggins, C.J. et al. (2013) [160] |
CHOP | Stimulation of pro-senescence protein p21 expression | Inoue, Y. et al. (2017) [165] | |
NRF2 | Senescence alleviation presumably through the expression of NRF2-target genes, which exert an anti-senescence effect | He, C.H. et al. (2001) [170] | |
ATF3 | Not stated | Stimulation of replicative senescence through upregulation of pro-senescence proteins like p16 and p21 | Zhang, C. et al. (2021) [139] |
ATF3 knockdown results in aggravated senescence in macrophages exposed to Pseudomonas aeruginosa | Zhao, Q. et al. (2021) [140] | ||
Aggravation of acrylamide-induced senescence by upregulation of p53 and p21 pro-senescent proteins in macrophages | Kim, K.-H. et al. (2015) [141] | ||
ATF4 | Not stated | Upregulation of pro-senescence protein p16 in senescent renal tubular epithelial cells | Liu, J. et al. (2015) [146] |
Upregulation of pro-senescence protein p16 in oxidative stress induces senescence in MEFs | Sakai, T. et al. (2019) [147] | ||
CHOP | Not stated | Senescence aggravation in alveolar epithelial cells from patients with idiopathic pulmonary fibrosis through enhancement of ROS generation and activation of the NF-κB pathway—factors promoting senescence | Jing, X. et al. (2022) [166] |
CEBPA | Not stated | Senescence aggravation by upregulation pro-senescence factors: CXCL1, CXCL5 and CXCL15 | Guan, Y. et al. (2020) [162] |
JDP2 | Not stated | Aggravation of MEFs replicative senescence by upregulation of p16 and p19 proteins | Nakade, K. et al. (2009) [178] |
FOS | Not stated | FOS expression is significantly increased during fibroblast replicative senescence | Seshadri, T. et al. (1990) [180] |
Not stated | FOS is upregulated in senescent T-cells, whether FOXO1 ensures the naïve state of T-cells through downregulation of FOS and FOSB | Delpoux, A. et al. (2021) [181] | |
MAF | Not stated | MAF disappears in senescent hADMSCs, leading to reduced osteogenic differentiation capacity | Chen P.-M., et al. (2015) [182] |
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Kalinin, A.; Zubkova, E.; Menshikov, M. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence. Int. J. Mol. Sci. 2023, 24, 17423. https://doi.org/10.3390/ijms242417423
Kalinin A, Zubkova E, Menshikov M. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence. International Journal of Molecular Sciences. 2023; 24(24):17423. https://doi.org/10.3390/ijms242417423
Chicago/Turabian StyleKalinin, Alexander, Ekaterina Zubkova, and Mikhail Menshikov. 2023. "Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence" International Journal of Molecular Sciences 24, no. 24: 17423. https://doi.org/10.3390/ijms242417423