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1.
Sci Adv ; 5(10): eaax6366, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31633027

RESUMO

Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

2.
J Bone Joint Surg Am ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31644522

RESUMO

BACKGROUND: Diagnosing periprosthetic joint infection (PJI) requires various laboratory and clinical criteria. The purpose of this study was to explore novel biomarkers that could rapidly diagnose PJI with high accuracy. METHODS: In this retrospective study of prospectively collected samples, 50 synovial fluid aspirates, 20 from the hip and 30 from the knee, were collected before surgery; 25 of the patients were diagnosed as having aseptic loosening (non-PJI) and 25, as having PJI according to the Musculoskeletal Infection Society criteria. A quadrupole orbital-trap mass spectrometry (MS) instrument was used to compare expression of proteins in patients with and without PJI. Proteins that were most efficacious for diagnosis of PJI were then determined using prediction analysis of microarray software and a random forest model. The most promising proteins were selected, and altered expression of these selected proteins was verified by ELISA (enzyme-linked immunosorbent assay) in an extended sample cohort. RESULTS: A total of 256 proteins were significantly upregulated (≥3.0-fold) and 14 proteins were downregulated in synovial fluid of patients with PJI compared with patients without PJI. The 3 most promising proteins were lactoferrin (LTF), polymorphonuclear leukocyte serine protease 3 (PRTN3), and myeloid nuclear differentiation antigen (MNDA). When MS was used for diagnosis of PJI, the area under the curve was 0.9888 for LTF, 0.9488 for PRTN3, and 0.9632 for MNDA. ELISA results verified that LTF, MNDA, and PRTN3 were sensitive, while LTF and MNDA were specific, for diagnosis of PJI. CONCLUSIONS: This proteomic study identified a previously noted protein and 2 novel candidate proteins as promising synovial fluid biomarkers for PJI diagnosis, and they should be further validated in future clinical trials. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

3.
J Exp Med ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636135

RESUMO

Follicular helper T (Tfh) cells provide essential help for humoral immune response. Transcriptional factor Bcl6 is the master regulator for Tfh generation and is induced very early after T cell activation in a CD28-dependent manner, but how CD28 signal promotes Bcl6 early expression remains unknown. Here we found that CD28 signal quickly induces expression of the H3K36me2 methytransferase Nsd2, which is required for Bcl6 expression as early as the first cell division after T cell activation. Nsd2 deficiency in T cells leads to decreased Bcl6 expression, impaired Tfh generation, compromised germinal center response, and delayed virus clearance. Ectopic Bcl6 expression rescues the Tfh defect of Nsd2 KO cells. ICOS signal is dispensable for early Nsd2 induction but required for sustained Nsd2 expression, which is critical for Tfh maintenance. Overexpression of Nsd2 increases Bcl6 expression and enhances Tfh generation; 4-mo-old mice even develop spontaneous Tfh. Overall, our study reveals Nsd2 as a critical epigenetic regulator for Tfh differentiation.

4.
J Chem Phys ; 151(14): 144710, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615251

RESUMO

We systematically explored the catalytic performance of a novel two dimensional material PtTe sheet for nitrogen reduction reaction (NRR) and hydrogen evolution reaction (HER) by using first-principles calculation. Although pristine PtTe shows poor NRR and HER activity, doping transition metal (TM) atoms into the lattice could effectively enhance the catalytic performance. Calculations show that four TM doped structures, including W-Pt18Te17, Ru-Pt18Te17, Mo-Pt18Te17, and Cr-Pt18Te17, are promising NRR catalysts on the prerequisite of whose HER activities are effectively suppressed. Moreover, the HER performance of the PtTe sheet could also be significantly improved with introduced TM atoms. In particular, Cu, Cr, Co, Ni, Mo, Rh, Ru, and Tc atoms supported by the PtTe sheet with Te-vacancy are promising HER electrocatalysts. The improved HER performance is attributed to the reduced adsorption free energy of the H atom. Both the doped TM atoms and the adjacent Pt atoms are effective active sites. Among all considered structures, Mo-, Cr-, and Ru-Pt18Te17 sheets boost catalytic activity for both NRR and HER. This study provides new design strategies to enhance the catalytic performance of the PtTe sheet for the NRR/HER.

5.
Structure ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31590942

RESUMO

Activation of cell surface receptor integrin has been extensively studied as the first key step to trigger cell adhesion, but the subsequent events, widely regarded as integrin "outside-in" signaling to form supramolecular complexes (focal adhesions [FAs]) to promote dynamic cell adhesion, remain poorly elucidated. Integrin activator kindlin-2 was recently found to associate with paxillin in nascent FAs, implicating an early yet undefined integrin outside-in signaling event. Here we show structurally that kindlin-2 recognizes paxillin via a distinct interface involving the ubiquitin-like kindlin-2 F0 domain and the paxillin LIM4 domain. The interface is adjacent to the membrane binding site of kindlin-2 F0, suggesting a mechanism for kindlin-2 to recruit paxillin to the membrane-proximal site where FA assembly is initiated. Disruption of the interface impaired the localization of paxillin, causing strong defects in FA assembly and cell migration. These data unveil a structural basis of the kindlin-2/paxillin interaction in controlling dynamic cell adhesion.

6.
J Cell Sci ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578239

RESUMO

Recruitment and tethering of talin to the plasma membrane initiate the process of integrin activation. Multiple factors including Rap1, RIAM, and PIP2 bind talin and have been proposed to regulate these processes, but not systematically analyzed. By expressing specific talin mutants into talin-null fibroblasts, we show that binding of talins F0 domain to Rap1 synergizes with membrane lipid binding of talins F2 domain during talin membrane targeting and integrin activation, whereas the interaction of the talin rod with RIAM was dispensable. We also characterized a second Rap1 binding site within the talin F1 domain by detailed NMR analysis. Interestingly, while talin F1 exhibited significantly weaker Rap1-binding affinity than talin F0, expression of a talin F1 Rap1-binding mutant inhibited cell adhesion, spreading, talin recruitment and integrin activation similarly as the talin F0 Rap1-binding mutant. Moreover, the defects became significantly stronger when both Rap1-binding sites were mutated. In conclusion, our data suggest a model in which cooperative binding of Rap1 to the talin F0 and F1 domains synergizes with membrane PIP2 binding to spatiotemporally position and activate talin to regulate integrin activity.

7.
Nat Cell Biol ; 21(9): 1152-1163, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481791

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its δ isoform is predominant in the heart. Excessive CaMKII activation plays a pivotal role in the pathogenesis of severe heart conditions, including myocardial infarction, cardiomyopathy and heart failure. However, the identity of CaMKII splice variants and the mechanism(s) underlying CaMKII-mediated cardiac pathology remain elusive. Here, we show that CaMKII-δ9, the most abundant CaMKII-δ splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-δ9, but not the previously well-studied CaMKII-δ2 and CaMKII-δ3, targets the ubiquitin-conjugating enzyme E2T (UBE2T) for phosphorylation and degradation, disrupting UBE2T-dependent DNA repair and leading to the accumulation of DNA damage and genome instability. These findings not only reveal a crucial role of CaMKII in the regulation of DNA repair, but also mark the CaMKII-δ9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.

8.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(8): 950-956, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31511216

RESUMO

OBJECTIVE: To investigate the effects of different doses of propofol on myelin basic protein (MBP) synthesis and myelination of oligodendrocytes in neonatal SD rats. METHODS: A total of 57 neonatal SD rats (7 days old) were randomly divided into control group (n=13), vehicle (fat emulsion) group (n=5), and 25, 50 and 100 mg/kg propofol groups (n=13 in each group). Eight hours after a single intraperitoneal injection of propofol or the vehicle, the rats were examined for expressions of mbp mRNA, caspase-3 mRNA, cleaved caspase-3 and MBP in the brain tissues using qPCR and Western blotting. Immunofluorescence assay was used to detect the apoptosis of the oligodendrocytes at 8 h after the injection and the myelination of the corpus callosum and internal capsule at 24 h. RESULTS: Compared with the control group, the neonatal rats with propofol injections showed significantly down-regulated expressions of mbp mRNA and MBP protein in the brain tissue (P < 0.05). Propofol dose-dependently increased the transcription level of caspase-3 and the protein levels of cleaved caspase-3 at 8 h after the injection (P < 0.05). Propofol injection significantly increased the apoptosis of the oligodendrocytes, and the effect was significantly stronger in 50 and 100 mg/kg groups than in 25 mg/kg group (P < 0.05). At 24 h after propofol injection, myelin formation was significantly decreased in the corpus callosum of the neonatal rats in 100 mg/kg propofol group and in the internal capsule in 50 and 100 mg/kg groups (P < 0.05). CONCLUSIONS: In neonatal SD rats, propofol can dose-dependently promote oligodendrocyte apoptosis, decrease MBP expressions in the brain, and suppress myelin formation in the corpus callosum and the internal capsule.


Assuntos
Oligodendroglia , Animais , Proteína Básica da Mielina , Propofol , RNA Mensageiro , Ratos , Ratos Sprague-Dawley
9.
Cell Death Dis ; 10(9): 655, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506433

RESUMO

Obesity is a major epigenetic cause for colorectal cancer (CRC). Leptin is implicated in obesity-associated CRC, but the underlying mechanism remains unclear. The current study identified over-expression of metallopanstimulin-1 (MPS-1) in CRC patients through microarray and histological analysis, especially in obese CRC patients. MPS-1 was correlated with advanced tumor stage, suggesting its association with CRC progression. In addition, MPS-1 over-expression was associated with poor overall survival (OS) in obese CRC patients, but not in their non-obese counterparts, suggesting its potential as a prognostic marker of obese CRC patients. MPS-1 expression was positively associated with circulating leptin levels in CRC patients, especially in obese cases. Functional experiments demonstrated that MPS-1 silencing inhibited tumor proliferation and colony formation, and induced apoptosis of CRC cells in vitro. Converse results were obtained from the experiments with MPS-1 over-expression. Mechanistically, MPS-1 executed its action through induction of c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moreover, the promotion effect of MPS-1 on CRC progression was modulated by leptin. In vivo studies demonstrated that MPS-1 silencing suppressed tumor growth of CRC via inhibiting JNK/c-Jun signaling. Collectively, this study indicates that MPS-1 promotes leptin-induced CRC via activating JNK/c-Jun pathway. MPS-1 might represent a potent candidate for the treatment and prognostic prediction of obesity-associated CRC.

10.
Opt Lett ; 44(18): 4471-4474, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31517909

RESUMO

We report a compact, long nanosecond (ns) pulse duration stretched laser source by a multi-pass cavity (MPC). Based on the combination of the MPC and pump power, a high-power high beam quality 1064 nm Q-switched Nd:YAG laser with a pulse duration adjustable over the range of 160-1000 ns was obtained at a pulse repetition frequency of 10 kHz for the first time, to the best of our knowledge. At a typical pulse width of 560 ns, an average output power of 10.6 W was successfully achieved. The beam quality factor M2 was measured to be 1.45 with a good Gaussian mode.

11.
Nat Commun ; 10(1): 4157, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519887

RESUMO

Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity. However, how its kinase activity is regulated remains poorly understood. Here, we generate Ripk1K376R/K376R knock-in mice in which the Lys(K)63-linked ubiquitination of RIPK1 is impaired. The knock-in mice display an early embryonic lethality due to massive cell death that is resulted from reduced TAK1-mediated suppression on RIPK1 kinase activity and forming more TNFR1 complex II in Ripk1K376R/K376R cells in response to TNFα. Although TNFR1 deficiency delays the lethality, concomitant deletion of RIPK3 and Caspase8 fully prevents embryonic lethality of Ripk1K376R/K376R mice. Notably, Ripk1K376R/- mice are viable but develop severe systemic inflammation that is mainly driven by RIPK3-dependent signaling pathway, indicating that K63-linked ubiquitination on Lys376 residue of RIPK1 also contributes to inflammation process. Together, our study reveals the mechanism by which K63-linked ubiquitination on K376 regulates RIPK1 kinase activity to control cell death programs.

12.
Nat Commun ; 10(1): 4353, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554795

RESUMO

Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.

13.
Sheng Wu Gong Cheng Xue Bao ; 35(9): 1715-1722, 2019 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-31559753

RESUMO

The liver is the metabolic center of mammalian body. Systematic study on liver's proteome expression under different physiological and pathological conditions helps us understand the functional mechanisms of the liver. With the rapid development of liquid chromatography tandem mass spectrometry technique, numerous studies on liver physiology and pathology features produced a large number of proteomics data. In this paper, 834 proteomics experiments of mouse liver were systematically collected and the mouse liver proteome database (Mouse Liver Portal, http://mouseliver.com) was established. The Mouse Liver Portal contains the liver's proteomics data under different physiology and pathology conditions, such as different gender, age, circadian rhythm, cell type and different phase of partial hepatectomy, non-alcoholic fatty liver. This portal provides the changes in proteins' expression in different conditions of the liver, differently expressed proteins and the biological processes which they are involved in, potential signal transduction and regulatory networks. As the most comprehensive mouse liver proteome database, it can provide important resources and clues for liver biology research.


Assuntos
Proteoma , Proteômica , Animais , Cromatografia Líquida , Bases de Dados Factuais , Fígado , Camundongos
14.
Cell Res ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501519

RESUMO

The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.

15.
Cell Commun Signal ; 17(1): 101, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429758

RESUMO

BACKGROUND: Previously sharpin has been identified as an endogenous inhibitor of ß1-integrin activation by directly binding to a conserved region in the cytoplasmic tails (CTs) of the integrin ß1-associated α subunits. METHODS: Here we employed biochemical approaches and cellular analyses to evaluate the function and molecular mechanism of the sharpin-kindlin-1 complex in regulating ß1-integrin activation. RESULTS: In this study, we found that although the inhibition of sharpin on ß1-integrin activation could be confirmed, sharpin had no apparent effect on integrin αIIbß3 activation in CHO cell system. Notably, a direct interaction between sharpin and the integrin ß1 CT was detected, while the interaction of sharpin with the integrin αIIb and the ß3 CTs were substantially weaker. Importantly, sharpin was able to inhibit the talin head domain binding to the integrin ß1 CT, which can mechanistically contribute to inhibiting ß1-integrin activation. Interestingly, we also found that sharpin interacted with kindlin-1, and the interaction between sharpin and the integrin ß1 CT was significantly enhanced when kindlin-1 was present. Consistently, we observed that instead of acting as an activator, kindlin-1 actually suppressed the talin head domain mediated ß1-integrin activation, indicating that kindlin-1 may facilitate recruitment of sharpin to the integrin ß1 CT. CONCLUSION: Taken together, our findings suggest that sharpin may complex with both kindlin-1 and the integrin ß1 CT to restrict the talin head domain binding, thus inhibiting ß1-integrin activation.

16.
J Proteome Res ; 18(10): 3715-3730, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31442056

RESUMO

Ligand binding to the cell surface receptors initiates signaling cascades that are commonly transduced through a protein-protein interaction (PPI) network to activate a plethora of response pathways. However, tools to capture the membrane PPI network are lacking. Here, we describe a cross-linking-aided mass spectrometry workflow for isolation and identification of signal-dependent epidermal growth factor receptor (EGFR) proteome. We performed protein cross-linking in cell culture at various time points following EGF treatment, followed by immunoprecipitation of endogenous EGFR and analysis of the associated proteins by quantitative mass spectrometry. We identified 140 proteins with high confidence during a 2 h time course by data-dependent acquisition and further validated the results by parallel reaction monitoring. A large proportion of proteins in the EGFR proteome function in endocytosis and intracellular protein transport. The EGFR proteome was highly dynamic with distinct temporal behavior; 10 proteins that appeared in all time points constitute the core proteome. Functional characterization showed that loss of the FYVE domain-containing proteins altered the EGFR intracellular distribution but had a minor effect on EGFR proteome or signaling. Thus, our results suggest that the EGFR proteome include functional regulators that influence EGFR signaling and bystanders that are captured as the components of endocytic vesicles. The high-resolution spatiotemporal information of these molecules facilitates the delineation of many pathways that could determine the strength and duration of the signaling, as well as the location and destination of the receptor.

17.
Nucleic Acids Res ; 47(17): 9053-9068, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31400111

RESUMO

Faithful inheritance of DNA methylation across cell division requires DNMT1 and its accessory factor UHRF1. However, how this axis is regulated to ensure DNA methylation homeostasis remains poorly understood. Here we show that SET8, a cell-cycle-regulated protein methyltransferase, controls protein stability of both UHRF1 and DNMT1 through methylation-mediated, ubiquitin-dependent degradation and consequently prevents excessive DNA methylation. SET8 methylates UHRF1 at lysine 385 and this modification leads to ubiquitination and degradation of UHRF1. In contrast, LSD1 stabilizes both UHRF1 and DNMT1 by demethylation. Importantly, SET8 and LSD1 oppositely regulate global DNA methylation and do so most likely through regulating the level of UHRF1 than DNMT1. Finally, we show that UHRF1 downregulation in G2/M by SET8 has a role in suppressing DNMT1-mediated methylation on post-replicated DNA. Altogether, our study reveals a novel role of SET8 in promoting DNA methylation homeostasis and identifies UHRF1 as the hub for tuning DNA methylation through dynamic protein methylation.

18.
Cancer Res ; 79(17): 4387-4398, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289136

RESUMO

Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3ß-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7. SIGNIFICANCE: These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.

19.
Int J Cancer ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269234

RESUMO

Colorectal cancer is one of the most common cancers all over the world. Colorectal cancer stem cells (CSCs) drive colorectal tumorigenesis and metastasis, while, the biology of colorectal CSCs remains unclear. Circular RNAs (circRNAs) emerge as critical regulators in various biological processes, but their roles in colorectal CSCs remain indistinct. Here we identified circLgr4 as a highly expressed circRNA in colorectal tumors and colorectal CSCs. circLgr4 knockdown inhibited colorectal CSC self-renewal, colorectal tumorigenesis and invasion, and circLgr4 overexpression played opposite roles. With peptide-coding capacity, circLgr4 drove the self-renewal of colorectal CSCs through peptide-dependent manner. circLgr4-derived peptide interacted with and activated Lgr4, which further promoted the activation of Wnt/ß-catenin signaling. circLgr4-peptide-Lgr4 axis could be used to target colorectal CSCs and colorectal tumorigenesis. Our work revealed a functional circRNA in colorectal CSCs, adding a novel layer for circRNA function and colorectal CSC regulation. This article is protected by copyright. All rights reserved.

20.
Nat Cell Biol ; 21(8): 1027-1040, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332347

RESUMO

Sensing cytosolic DNA through the cGAS-STING pathway constitutes a widespread innate immune mechanism to monitor cellular damage and microbial invasion. Evading this surveillance is crucial in tumorigenesis, but the process remains largely unexplored. Here, we show that the receptor tyrosine kinase HER2 (also known as ErbB-2 or Neu) potently inhibits cGAS-STING signalling and prevents cancer cells from producing cytokines, entering senescence and undergoing apoptosis. HER2, but not EGFR, associates strongly with STING and recruits AKT1 (also known as PKB) to directly phosphorylate TBK1, which prevents the TBK1-STING association and TBK1 K63-linked ubiquitination, thus attenuating STING signalling. Unexpectedly, we observed that DNA sensing robustly activates the HER2-AKT1 axis, resulting in negative feedback. Accordingly, genetic or pharmacological targeting of the HER2-AKT1 cascade augments damage-induced cellular senescence and apoptosis, and enhances STING-mediated antiviral and antitumour immunity. Thus, our findings reveal a critical function of the oncogenic pathway in innate immune regulation and unexpectedly connect HER2-AKT1 signalling to the surveillance of cellular damage and antitumour immunity.

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