Cytoplasmic STAT3 Represses Autophagy by Inhibiting PKR Activity

Shen, Shensi; Niso-Santano, Mireia; Adjemian, Sandy; Takehara, Tetsuo; Malik, Shoaib Ahmad; Minoux, Hervé; Souquère, Sylvie; Mariño, Guillermo; Lachkar, Sylvie; Senovilla, Laura; Galluzzi, Lorenzo; Kepp, Oliver; Pierron, Gérard; Maiuri, Maria Chiara; Hikita, Hayato; Kroemer, Romano T.

doi:10.1016/j.molcel.2012.09.013

Cited by 238 publications

(191 citation statements)

References 55 publications

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“…Wild-type STAT3 and nonphosphorylatable STAT3 Y705F transfected into U2OS cells inhibit baseline as well as starvation-induced EIF2A phosphorylation, further confirming this hypothesis. 14 The phosphorylation of EIF2A mediates general translational arrest and promotes the selective transactivation of stress response genes. Cells carrying a nonphosphorylatable EIF2A (S51A) mutant fail to induce autophagy in starvation conditions, suggesting that EIF2A phosphorylation of serine 51 plays a major role in autophagy regulation.…”

Section: Regulation Of Autophagy By Cytoplasmic Stat3mentioning

confidence: 99%

“…A wide range of RTKs phosphorylate STAT3 directly or via SRC kinase, and several studies have proven that blocking kinases such as KDR, PDGFRB, and ALK results in enhanced autophagy by subsequent inhibition of the STAT3 pathway (Table 3). 14,41,42,50,[74][75][76][77][78][79][80][81][82][83] Currently, several JAK-STAT inhibitors are being examined in clinical trials for cancer therapy. For example, in a phase II clinical trial to treat metastatic pancreatic cancer, ruxolitinib together with capecitabine showed a benefit for overall survival and progression-free survival compared with a placebo plus capecitabine used in second-line therapy, promoting the application of JAK-STAT inhibitors in cancer therapy.…”

Section: Implication Of Stat3-regulated Autophagy In Cancer Therapeuticsmentioning

confidence: 99%

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The role of STAT3 in autophagy

et al. 2015

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Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

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Section: Regulation Of Autophagy By Cytoplasmic Stat3mentioning

confidence: 99%

Section: Implication Of Stat3-regulated Autophagy In Cancer Therapeuticsmentioning

confidence: 99%

The role of STAT3 in autophagy

et al. 2015

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“…17,[27][28][29] Antigen retrieval was performed by incubating slides in citrate buffer (pH 7.3) for 20 min at 98 C and cooling them for 30 min, at room temperature (RT). The sections were mounted on Shandon Sequenza coverplates (Thermo Fisher Scientific, 72-199-50) in distilled water.…”

Section: Phospho-eif2amentioning

confidence: 99%

The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Semeraro¹,

Adam

Stoll³

et al. 2016

OncoImmunology

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In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2a (eIF2a, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8 C cytotoxic T lymphocytes and FOXP3 C regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2a phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8 C infiltrate and the CD8 C /FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8 C /FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8 C infiltrate as well as an unfavorable CD8 C /FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8 C /FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.

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“…16 Moreover, PA causes the disruption of inhibitory signal transducer and activator of transcription 3-RNA-dependent protein kinase interactions, which facilitates autophagy induction. 17 In contrast, a high-fat diet (HFD) downregulates autophagy by reducing autophagosome/lysosome fusion, 18 as well as by decreasing the number and the acidity of lysosomes. 19 The conflicting results may be attributed to differences in cell types, observation period, FFAs concentration and, more likely, difficulty in monitoring autophagic flux in vivo.…”

mentioning

confidence: 99%

High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney

Yamamoto¹,

Takabatake²,

Takahashi³

et al. 2016

JASN

215

194

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Excessive fat intake contributes to the progression of metabolic diseases via cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.

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Cytoplasmic STAT3 Represses Autophagy by Inhibiting PKR Activity

Cited by 238 publications

References 55 publications

The role of STAT3 in autophagy

The role of STAT3 in autophagy

The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney

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Cytoplasmic STAT3 Represses Autophagy by Inhibiting PKR Activity

Cited by 238 publications

References 55 publications

The role of STAT3 in autophagy

The role of STAT3 in autophagy

The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney

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The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ