Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity
Open accessAbstract
In a screen designed to identify novel inducers of autophagy, we discovered that STAT3 inhibitors potently stimulate the autophagic flux. Accordingly, genetic inhibition of STAT3 stimulated autophagy in vitro and in vivo, while overexpression of STAT3 variants, encompassing wild-type, nonphosphorylatable, and extranuclear STAT3, inhibited starvation-induced autophagy. The SH2 domain of STAT3 was found to interact with the catalytic domain of the eIF2α kinase 2 EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic inhibition of STAT3 stimulated the activating phosphorylation of PKR and consequent eIF2α hyperphosphorylation. Moreover, PKR depletion inhibited autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like palmitate. STAT3-targeting chemicals and palmitate caused the disruption of inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2α phosphorylation, which facilitates autophagy induction. These results unravel an unsuspected mechanism of autophagy control that involves STAT3 and PKR as interacting partners.
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Cytoplasmic STAT3 inhibits autophagy by inhibiting eukaryotic translation initiation factor 2-α kinase 2 activity, by binding to its catalytic domain, thereby preventing formation of phosphorylated eIF2α.
“In contrast to nuclear STAT3, cytoplasmic STAT3 inhibits autophagy by inhibiting eukaryotic translation initiation factor 2-α kinase 2 activity, by binding to its catalytic domain, thereby inhibiting its enzymatic activity, thereby preventing formation of phosphorylated eukaryotic translation initiation factor 2-α, a known autophagy activator (Shen et al., 2012).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Shen et al., 2012
Cites
Autophagy and the Integrated Stress Response
Kroemer, G., Mariño, G., & Levine, B. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.023 · Cited by 3,506 · see citing works
Self-citationAutophagy in immunity and inflammation
Levine, B., Mizushima, N., & Virgin, H. W. (2011) · Nature · doi:10.1038/nature09782 · Cited by 3,289 · see citing works
Regulation of autophagy by cytoplasmic p53
Tasdemir, E., Maiuri, M. C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1730 · Cited by 1,132 · see citing works
Self-citationFunction of Mitochondrial Stat3 in Cellular Respiration
Wegrzyn, J., Potla, R., Chwae, Y.-J., Sepuri, N. B. V., Zhang, Q., Koeck, T., Derecka, M., Szczepanek, K., Szelag, M., Gornicka, A., et al. (2009) · Science · doi:10.1126/science.1164551 · Cited by 1,014 · see citing works
HSV-1 ICP34.5 Confers Neurovirulence by Targeting the Beclin 1 Autophagy Protein
Orvedahl, A., Alexander, D., Tallóczy, Z., Sun, Q., Wei, Y., Zhang, W., Burns, D., Leib, D. A., & Levine, B. (2007) · Cell Host & Microbe · doi:10.1016/j.chom.2006.12.001 · Cited by 857 · see citing works
Morselli, E., Maiuri, M. C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S. A., Vitale, I., et al. (2010) · Cell Death & Disease · doi:10.1038/cddis.2009.8 · Cited by 613 · see citing works
Self-citationBiogenesis and Cargo Selectivity of Autophagosomes
Weidberg, H., Shvets, E., & Elazar, Z. (2011) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052709-094552 · Cited by 466 · see citing works
Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation
Yang, J., Chatterjee-Kishore, M., Staugaitis, S. M., Nguyen, H., Schlessinger, K., Levy, D. E., & Stark, G. R. (2005) · Cancer Research · doi:10.1158/0008-5472.939.65.3 · Cited by 405 · see citing works
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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Self-citationKlionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationAutophagy in infection, inflammation and immunity
Deretic, V., Saitoh, T., & Akira, S. (2013) · Nature Reviews Immunology · doi:10.1038/nri3532 · Cited by 1,919 · see citing works
Metabolic control of autophagy
Galluzzi, L., Pietrocola, F., Levine, B., & Kroemer, G. (2014) · Cell · doi:10.1016/j.cell.2014.11.006 · Cited by 855 · see citing works
Self-citationThe role of STAT3 in autophagy
You, L., Wang, Z., Li, H., Shou, J., Jing, Z., Xie, J., Sui, X., Pan, H., & Han, W. (2015) · Autophagy · doi:10.1080/15548627.2015.1017192 · Cited by 515 · see citing works
Autophagy and cellular immune responses
Ma, Y., Galluzzi, L., Zitvogel, L., & Kroemer, G. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.017 · Cited by 447 · see citing works
Self-citationBharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…by inhibiting eukaryotic translation initiation factor 2-a kinase 2 activity, by binding to its catalytic domain, thereby inhibiting its enzymatic activity, thereby preventing formation of phosphorylated eukaryotic translation initiation factor 2-a, a known autophagy activator (Shen et al., 2012).”
BackgroundOrganelle-Specific Initiation of Autophagy
Sica, V., Galluzzi, L., Bravo-San Pedro, J. M., Izzo, V., Maiuri, M. C., & Kroemer, G. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.021 · Cited by 205 · see citing works
Self-citationThe complex STATes of astrocyte reactivity: How are they controlled by the JAK-STAT3 pathway?
Ceyzériat, K., Abjean, L., Carrillo-de Sauvage, M.-A., Ben Haim, L., & Escartin, C. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.05.043 · Cited by 185 · see citing works
Genini, D., Brambilla, L., Laurini, E., Merulla, J., Civenni, G., Pandit, S., D'Antuono, R., Perez, L., Levy, D. E., Pricl, S., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615730114 · Cited by 106 · see citing works
Wu, Q., Tian, A.-L., Li, B., Leduc, M., Forveille, S., Hamley, P., Galloway, W., Xie, W., Liu, P., Zhao, L., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002722 · Cited by 83 · see citing works
Self-citationPapaioannou, I., Xu, S., Denton, C. P., Abraham, D. J., & Ponticos, M. (2018) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-06-0342 · Cited by 64 · see citing works
Zhang, X.-W., Mi, S., Li, Z., Zhou, J.-C., Xie, J., Hua, F., Li, K., Cui, B., Lv, X.-X., Yu, J.-J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.14266 · Cited by 48 · see citing works
CD44 connects autophagy decline and ageing in the vascular endothelium
Zhang, L., Yang, P., Chen, J., Chen, Z., Liu, Z., Feng, G., Sha, F., Li, Z., Xu, Z., Huang, Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41346-y · Cited by 45 · see citing works
Pensa, S., Lloyd‐Lewis, B., Sargeant, T. J., Resemann, H. K., Kahn, C. R., & Watson, C. J. (2014) · The FEBS Journal · doi:10.1111/febs.13035 · Cited by 28 · see citing works
- Authors
- Shen, S., Niso-Santano, M., Adjemian, S., Takehara, T., Malik, S. A., Minoux, H., Souquere, S., Mariño, G., Lachkar, S., Senovilla, L., Galluzzi, L., Kepp, O., Pierron, G., Maiuri, M. C., Hikita, H., Kroemer, R., & Kroemer, G.
- Affiliations
- Université Paris-Sud (FR)
- The University of Osaka (JP)
- Sanofi (France) (FR)
- Institut Gustave Roussy (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Kroemer, Guido
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 48
- Issue
- 5
- Pages
- 667-680
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1968936285
- Cited by
- 285
- References
- 8
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 13 · 2023: 17 · 2022: 20 · 2021: 20 · 2020: 29 · 2019: 22 · 2018: 22 · 2017: 22 · 2016: 27 · 2015: 26 · 2014: 31 · 2013: 8 · 2012: 2
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repository University of Extremadura (University of Extremadura) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- STAT3, autophagy, PKR, eIF2α phosphorylation, autophagic flux, STAT3 inhibitor, palmitate, free fatty acids, starvation-induced autophagy, SH2 domain
- MeSH terms
- Animals, Autophagy, Cytoplasm, Enzyme Activation, Humans, Male, Mice, Inbred C57BL, Phosphorylation, Protein Conformation, Recombinant Fusion Proteins, Time Factors, Transfection, Signal Transduction, Eukaryotic Initiation Factor-2, Mice, Knockout, src Homology Domains, Palmitic Acid, eIF-2 Kinase, Catalytic Domain, Protein Interaction Mapping, RNA Interference, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Protein Interaction Domains and Motifs, Molecular Docking Simulation
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