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Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation. AMPK, once activated, directly phosphorylates TBK1 at S511, which triggers IRF3 recruitment and the assembly of MAVS or STING signalosomes. Consistently, ablation or inhibition of AMPK, knockin of TBK1-S511A, or increased glucose levels compromised nucleic acid sensing, while boosting AMPK-TBK1 cascade by AICAR or TBK1-S511E knockin improves antiviral immunity substantially in various animal models. Thus, we identify TBK1 as an AMPK substrate, reveal the molecular mechanism coupling a dual sensing of glucose and nuclei acids, and report its physiological necessity in antiviral defense.
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Proteínas Quinases Ativadas por AMP , Ácidos Nucleicos , Animais , Proteínas Quinases Ativadas por AMP/genética , Imunidade Inata , Antivirais , GlucoseRESUMO
Missense mutations of the tumor suppressor Neurofibromin 2 (NF2/Merlin/schwannomin) result in sporadic to frequent occurrences of tumorigenesis in multiple organs. However, the underlying pathogenicity of NF2-related tumorigenesis remains mostly unknown. Here we found that NF2 facilitated innate immunity by regulating YAP/TAZ-mediated TBK1 inhibition. Unexpectedly, patient-derived individual mutations in the FERM domain of NF2 (NF2m) converted NF2 into a potent suppressor of cGAS-STING signaling. Mechanistically, NF2m gained extreme associations with IRF3 and TBK1 and, upon innate nucleic acid sensing, was directly induced by the activated IRF3 to form cellular condensates, which contained the PP2A complex, to eliminate TBK1 activation. Accordingly, NF2m robustly suppressed STING-initiated antitumor immunity in cancer cell-autonomous and -nonautonomous murine models, and NF2m-IRF3 condensates were evident in human vestibular schwannomas. Our study reports phase separation-mediated quiescence of cGAS-STING signaling by a mutant tumor suppressor and reveals gain-of-function pathogenesis for NF2-related tumors by regulating antitumor immunity.
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Imunidade Inata , Proteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Neoplasias/metabolismo , Neurofibromina 2/metabolismo , Nucleotidiltransferases/metabolismo , Evasão Tumoral , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neurofibromina 2/genética , Nucleotidiltransferases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, YAP moves in and out of the nucleus. The pathophysiological mechanisms regulating YAP subcellular localization after myocardial infarction remain poorly defined. METHODS: We identified YAP acetylation at site K265 by in vitro acetylation followed by mass spectrometry analysis. We used adeno-associated virus to express YAP-containing mutations that either abolished acetylation (YAP-K265R) or mimicked acetylation (YAP-K265Q) and studied how acetylation regulates YAP subcellular localization in mouse hearts. We generated a cell line with YAP-K265R mutation and investigated the protein-protein interactors by YAP immunoprecipitation followed by mass spectrometry, then validated the YAP interaction in neonatal rat ventricular myocytes. We examined colocalization of YAP and TUBA4A (tubulin α 4A) by superresolution imaging. Furthermore, we developed YAP-K265R and αMHC-MerCreMer (MCM); Yap-loxP/K265R mutant mice to examine the pathophysiological role of YAP acetylation in cardiomyocytes during cardiac regeneration. RESULTS: We found that YAP is acetylated at K265 by CBP (CREB-binding protein)/P300 (E1A-binding protein P300) and is deacetylated by nicotinamide phosphoribosyltransferase/nicotinamide adenine dinucleotide/sirtuins axis in cardiomyocytes. After myocardial infarction, YAP acetylation is increased, which promotes YAP cytoplasmic localization. Compared with controls, mice that were genetically engineered to express a K265R mutation that prevents YAP K256 acetylation showed improved cardiac regenerative ability and increased YAP nuclear localization. Mechanistically, YAP acetylation facilitates its interaction with TUBA4A, a component of the microtubule network that sequesters acetylated YAP in the cytoplasm. After myocardial infarction, the microtubule network increased in cardiomyocytes, resulting in the accumulation of YAP in the cytoplasm. CONCLUSIONS: After myocardial infarction, decreased sirtuin activity enriches YAP acetylation at K265. The growing TUBA4A network sequesters acetylated YAP within the cytoplasm, which is detrimental to cardiac regeneration.
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The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Fosfatase 2C/metabolismo , Regeneração/fisiologia , Fatores de Transcrição/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Colite/patologia , Humanos , Intestinos/fisiologia , Regeneração Hepática/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organoides , Proteína Fosfatase 2C/genética , Transdução de Sinais , Proteínas de Sinalização YAPRESUMO
Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we found that mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, its occupancy on chromatin, and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies.
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Citosol/imunologia , Imunidade Inata/genética , Fator Regulador 3 de Interferon/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Infecções por Rhabdoviridae/enzimologia , Infecções por Rhabdoviridae/imunologia , Animais , Linhagem Celular , Ativação Enzimática/genética , Células HEK293 , Humanos , Fator Regulador 3 de Interferon/genética , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ligação Proteica , Serina-Treonina Quinase 3 , Vesiculovirus/imunologia , Peixe-Zebra/imunologiaRESUMO
Polaprezinc (PZ) plays a role in the protection of gastric mucosa and inhibiting Helicobacter pylori (H. pylori) growth in vitro. The objective of this study was to determine the protective effects of PZ on human gastric epithelial cells (GES-1) against H. pylori-induced damage, while also examining heat shock protein 70 (HSP70) as a potential underlying factor in this protection. Our findings revealed that PZ exerted bactericidal effects against H. pylori strains. We also observed that PZ mitigated the H. pylori-induced damage to GES-1 cells by increasing cell viability, reducing LDH release, and decreasing the secretion of pro-inflammatory factors such as MCP-1 and IL-6. Co-culturing PZ with GES-1 cells significantly up-regulated the GES-1 HSP70 expression in both a time and dose-dependent manner. Pre-incubating (for 12 h) or co-culturing (for 24 h) GES-1 cells with PZ reversed the down-regulation of HSP70 in GES-1 cells caused by H. pylori infection. However, when quercetin was used to inhibit the up-regulation of HSP70 in GES-1 cells, the protective effect of PZ on GES-1 cells was significantly reduced. Based on the results of this study, PZ exhibits a protective role on GES-1 cells against H. pylori injury, as well as a direct bactericidal effect on H. pylori. HSP70 is involved in the PZ-driven host cell protection against H. pylori injury. These findings provide insight into alternative strategies for H. pylori treatment.
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Infecções por Helicobacter , Helicobacter pylori , Compostos Organometálicos , Humanos , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP70/farmacologia , Citoproteção , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Células Epiteliais/metabolismo , Infecções por Helicobacter/metabolismo , Mucosa GástricaRESUMO
BACKGROUND: Estimates of survival in the older can be of benefit in various facets, particularly in medical and individual decision-making. We aim to validate the value of a combination of nutrition status evaluation and comorbidity assessment in predicting long-term survival among community-dwelling older. METHODS: The Charlson Comorbidity Index (CCI) was applied for comprehensive evaluation of comorbidities. Participants were classified into CCI score ≤ 2 and ≥ 3 subgroups. Nutritional status was assessed by using Mini Nutritional Assessment-Short Form (MNA-SF) and Geriatric Nutritional Risk Index (GNRI) evaluations. Mortality rates and survival curves over a 5-year period were compared among subgroups classified by CCI and/or MNA-SF/GNRI evaluations. RESULTS: A total of 1033 elderly male participants were enrolled in this study, with an average age of 79.44 ± 8.61 years. 108 deceased participants (10.5%) were identified during a follow-up of 5 years. Cox proportional hazards regression analysis showed that age, CCI, MNA-SF and GNRI were independent predictors of 5-year all-cause death in this cohort. Compared to those with normal nutrition status and CCI ≤ 2, the subgroup at risk of malnutrition and CCI ≥ 3 had a significantly higher 5-year all-cause mortality rate (HR = 4.671; 95% CI:2.613-8.351 for MNA-SF and HR = 7.268; 95% CI:3.401-15.530 for GNRI; P < 0.001 for both). Receiver operating characteristic curve analysis demonstrated that a combination of either MNA-SF or GNRI with CCI had significantly better performance than CCI, MNA-SF or GNRI alone in predicting all-cause death. CONCLUSION: The combination of nutritional assessment (MNA-SF or GNRI) with CCI can significantly improve the predictive accuracy of long-term mortality outcomes among community-dwelling older males.
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Desnutrição , Estado Nutricional , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Vida Independente , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Desnutrição/complicações , Avaliação Nutricional , Curva ROC , Avaliação GeriátricaRESUMO
The development of reversible networks in elastomers provided unique inspiration for the design of advanced polymers with excellent properties. In this paper, we adopted an anionic melting method to introduce carboxylate groups into 1,2-polybutadiene (1,2-PB), using maleic anhydride as a modifier, and sodium hydride (NaH), calcium hydride (CaH2), and lithium aluminum hydride (LiAlH4) as metallization reagents. Na-Based, Ca-based, and Li/Al-based ionic bond networks were constructed in the covalently crosslinked 1,2-PB. The effects of the electronegativity and valence of the metal ions on the strength and reversible temperature of the ionic network were studied. Payne effect was shown by rheological tests, demonstrating the interactions between the ionic networks and rubber chains. The reforming temperature for these ionic networks was studied by stress-relaxation analysis, and shape memory experiments were performed based on these temperatures. This concept provides novel inspiration for the design of high-performance and temperature-adaptive elastomers.
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After myocardial infarction (MI), mammalian hearts do not regenerate, and the microenvironment is disrupted. Hippo signaling loss of function with activation of transcriptional co-factor YAP induces heart renewal and rebuilds the post-MI microenvironment. In this study, we investigated adult renewal-competent mouse hearts expressing an active version of YAP, called YAP5SA, in cardiomyocytes (CMs). Spatial transcriptomics and single-cell RNA sequencing revealed a conserved, renewal-competent CM cell state called adult (a)CM2 with high YAP activity. aCM2 co-localized with cardiac fibroblasts (CFs) expressing complement pathway component C3 and macrophages (MPs) expressing C3ar1 receptor to form a cellular triad in YAP5SA hearts and renewal-competent neonatal hearts. Although aCM2 was detected in adult mouse and human hearts, the cellular triad failed to co-localize in these non-renewing hearts. C3 and C3ar1 loss-of-function experiments indicated that C3a signaling between MPs and CFs was required to assemble the pro-renewal aCM2, C3+ CF and C3ar1+ MP cellular triad.
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RF-amide related peptide (RFRP) is the orthologue of gonadotropin-inhibitory hormone (GnIH) in mammals. The bodies of RFRP cell are located in the dorsomedial nucleus of the hypothalamus (DMH) and the fibers project to preoptic area (POA) and median eminence of the hypothalamus. Its receptor mainly distributes in hypothalamus. RFRP fibers project to GnRH cells to regulate mammalian reproduction axis. This paper reviews the progress of current researches on RFRP in regulation of animal behaviors, including reproduction, food intake, anxiety and stress response.
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Comportamento Animal/fisiologia , Neuropeptídeos/fisiologia , Reprodução/fisiologia , Animais , Mamíferos/fisiologiaRESUMO
Cardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM) 1 . Cardiac fibroblasts (CFs) are the primary cells that produce, degrade, and remodel ECM during homeostasis and tissue repair 2 . Upon injury, CFs gain plasticity to differentiate into myofibroblasts 3 and adipocyte-like 4,5 and osteoblast-like 6 cells, promoting fibrosis and impairing heart function 7 . How CFs maintain their cell state during homeostasis and adapt plasticity upon injury are not well defined. Recent studies have shown that Hippo signalling in CFs regulates cardiac fibrosis and inflammation 8-11 . Here, we used single-nucleus RNA sequencing (snRNA-seq) and spatially resolved transcriptomic profiling (ST) to investigate how the cell state was altered in the absence of Hippo signaling and how Hippo-deficient CFs interact with macrophages during cardiac fibrosis. We found that Hippo-deficient CFs differentiate into osteochondroprogenitors (OCPs), suggesting that Hippo restricts CF plasticity. Furthermore, Hippo-deficient CFs colocalized with macrophages, suggesting their intercellular communications. Indeed, we identified several ligand-receptor pairs between the Hippo-deficient CFs and macrophages. Blocking the Hippo-deficient CF-induced CSF1 signaling abolished macrophage expansion. Interestingly, blocking macrophage expansion also reduced OCP differentiation of Hippo-deficient CFs, indicating that macrophages promote CF plasticity.
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The Hippo pathway is an evolutionarily and functionally conserved signalling pathway that controls organ size by regulating cell proliferation, apoptosis, and differentiation. Emerging evidence has shown that the Hippo pathway plays critical roles in cardiac development, homeostasis, disease, and regeneration. Targeting the Hippo pathway has tremendous potential as a therapeutic strategy for treating intractable cardiovascular diseases, such as heart failure. In this review, we summarize the function of the Hippo pathway in the heart. Particularly, we highlight the post-translational modification of Hippo pathway components, including the core kinases LATS1/2 and their downstream effectors YAP/TAZ, in different contexts, which has provided new insights and avenues in cardiac research.
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Via de Sinalização Hippo , Transdução de Sinais , Apoptose , Diferenciação Celular , Proliferação de Células/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Purpose: Essential hypertension (EH) is an intricate non-communicable infirmity and lncRNAs are validated as essential mediators in EH. The study aimed to propose the expression pattern of FENDRR and miR-423-5p, substantiate the potential mechanism of FENDRR/miR-423-5p/Nox4 axis in EH. Patients and Methods: The expression of FENDRR and miR-423-5p was evaluated by qRT-PCR and the clinical significance was explored by the ROC curve. Pearson correlation indicated the relationship between FENDRR and miR-423-5p. The function of FENDRR and miR-423-5p on HUVECs was clarified by CCK-8 assay, Transwell assay, and flow cytometry. Western blot was used to assess the relative protein expression of Nox4. Results: FENDRR was highly expressed and miR-423-5p was lowly expressed in EH patients and a negative correlation between them was determined. FENDRR might serve as a predictive diagnosis in differentiating EH patients. Knockdown of FENDRR or overexpression of miR-423-5p showed expansionary effects in cell proliferation, cell migration, and inhibiting cell apoptosis. Meanwhile, miR-423-5p was determined as a target of FENDRR and mediated the function of FENDRR on HUVECs. Moreover, Nox4 is a down-streaming target gene of miR-423-5p. The protein expression of Nox4 was regulated by the alternation of miR-423-5p expression. Conclusion: FENDRR played an energetic role in EH and contributed to HUVECs dysfunction by restricting cell proliferation, suppressing cell migration, and accelerating cell apoptosis by manipulating the miR-423-5p/Nox4 axis.
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Rapid increase in resistance of Helicobacter pylori (H. pylori) has hindered antibiotics-based eradication efforts worldwide and raises the need for additional approaches. Here, we investigate the role of zinc-based compounds in inhibiting H. pylori growth and modulating antibiotic sensitivities, interrogate their downstream transcriptomic changes, and highlight the potential mechanism driving the observed effects. We showed that zinc acetate inhibited H. pylori growth and increased H. pylori sensitivity to levofloxacin. Transcriptomic profiling showed distinct gene expression patterns between zinc acetate treated groups versus controls. In particular, we independently replicated the association between zinc acetate treatment and increased ssrA expression. Knockdown of ssrA restored levofloxacin resistance to levels of the control group. In this study, we first demonstrated the role of zinc acetate in H. pylori growth and antibiotic sensitivities. Additionally, we explored the transcriptomic perturbations of zinc acetate followed by functional knockdown follow-up of differentially expressed ssrA, highlighting the role of tmRNA and trans-translation in H. pylori levofloxacin resistance. Our results provide alternative and complementary strategies for H. pylori treatment and shed light on the underlying mechanisms driving these effects. IMPORTANCE Helicobacter pylori (H. pylori) eradication plays an important role in gastric cancer prevention, but the antimicrobial resistance of H. pylori is fast becoming a growing concern. In this study, we investigated the role of zinc acetate in inhibiting H. pylori growth and modulating antibiotic sensitivities in vitro. Additionally, we explored the transcriptomic perturbations of zinc acetate followed by functional knockdown follow-up of differentially expressed ssrA, highlighting the role of tmRNA and trans-translation in H. pylori levofloxacin resistance. Our results open up a new horizon for the treatment of antibiotic-resistant H. pylori.
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Infecções por Helicobacter , Helicobacter pylori , Humanos , Levofloxacino/farmacologia , Helicobacter pylori/genética , Acetato de Zinco/farmacologia , Claritromicina/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Transcriptoma , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana/genéticaRESUMO
Efficacy of Helicobacter pylori (H. pylori) eradication therapy has declined due to rapid rises in antibiotic resistance. We investigated how increased temperature affected H. pylori (NCTC 11637) growth and its sensitivity to metronidazole in vitro. We performed transcriptomic profiling using RNA-sequencing to identify differentially expressed genes (DEGs) associated with increased temperature. Transcriptional pathways involved in temperature-driven metronidazole resistance changes were analyzed through bioinformatic and literature curation approaches. We showed that H. pylori growth was inhibited at 41°C and inhibition was more apparent with prolonged incubation. Resistance to metronidazole was also reduced-minimum inhibitory concentration for metronidazole decreased from > 256 µg/ml at 37°C to 8 µg/ml at 41°C after culturing for 3 days. RNA-sequencing results, which were highly concordant within treatment conditions, revealed more than one third of genes (583/1,552) to be differentially expressed at increased temperatures with similar proportions up and down-regulated. Quantitative real-time PCR validation for 8 out of 10 DEGs tested gave consistent direction in gene expression changes. We found enrichment for redox and oxygen radical pathways, highlighting a mechanistic pathway driving temperature-related metronidazole resistance. Independent literature review of published genes associated with metronidazole resistance revealed 46 gene candidates, 21 of which showed differential expression and 7 out of 9 DEGs associated with "redox" resistance pathways. Sanger sequencing did not detect any changes in genetic sequences for known resistance genes rdxA, frxA nor fdxB. Our findings suggest that temperature increase can inhibit the growth and reduce H. pylori resistance to metronidazole. Redox pathways are possible potential drivers in metronidazole resistance change induced by temperature. Our study provides insight into potential novel approaches in treating antibiotic resistant H. pylori.
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The diagnostic value of Helicobacter pylori stool antigen (HpSA) tests in elderly subjects remains unclear. The objective of this study was to assess the diagnostic accuracy of the immunochromatographic assay-based HpSA test in a male elderly cohort and identify factors affecting the accuracy. Data for asymptomatic elderly male citizens (≥65 years old) who received health checkups at the Chinese PLA General Hospital between July 2007 and November 2018 were collected. The diagnostic accuracy of the HpSA test was determined using the 13 C-urea breath test as a reference standard. Associations between baseline comorbidities and the accuracy of the HpSA test were analyzed. In total, 316 participants were enrolled, including 193 in the pre-treatment group (77.2 ± 7.8 years old) and 123 in the post-treatment group (78.7 ± 8.3 years old). The accuracy (91.5%, 91.2%, and 91.9%) and specificity (97.6%, 98.7%, and 96.0%) were high in all participants, pre- and post-treatment groups, respectively. However, sensitivities were only 68.7%, 65.1%, and 75.0%, respectively. In the pre-treatment group, constipation was associated with decreased sensitivity (p = 0.039), while colorectal polyps were associated with increased sensitivity (p = 0.010). Multivariate analysis indicated that constipation and colorectal polyps are independent factors for the sensitivity of HpSA in the pre-treatment group. The immunochromatographic assay-based HpSA test achieved high accuracy with high specificity but suboptimal sensitivity in the elderly male cohort. Constipation and colorectal polyps were negatively and positively associated with HpSA sensitivity, respectively, in the pre-treatment group.
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Antígenos de Bactérias/análise , Fezes/microbiologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Imunoensaio , Idoso , Idoso de 80 Anos ou mais , Testes Respiratórios , Comorbidade , Constipação Intestinal/complicações , Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Humanos , Pólipos Intestinais/complicações , Masculino , Sensibilidade e Especificidade , Ureia/análiseRESUMO
BACKGROUND: 17α-hydroxylase deficiency is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 gene. The major clinical presentation includes hypertension, hypokalemia, male pseudohermaphroditism and female gonadal dysplasia. Hundreds of pathogenic variants have been reported in this disorder, and some common mutations were found to be race-specific. CASE PRESENTATION: In this study, we reported 5 Chinese girls with 17α-hydroxylase deficiency from Henan Province. The patients all came to the hospital for hypertension, and they also presented with sexual infantilism. The average age of the patients was 14 years old, ranging from 12 to 17 years old. They all had reduced blood cortisol, estradiol (E2), and testosterone (TESTO) and increased adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). They all had the appearance of females; however, three of the chromosome karyotypes were 46XX, and two were 46XY. CONCLUSIONS: All of the patients carried a mutation on the 329 amino acid of CYP17A1 exon 6. By summarizing the currently known pathogenic mutations of 17α-hydroxylase deficiency, we demonstrated the prevalence of these gene mutations in Chinese Han and non-Chinese populations.
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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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Imunidade Inata/imunologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas de Membrana/imunologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptor ErbB-2/imunologia , Ubiquitinação/imunologiaRESUMO
Polychlorinated biphenyls (PCB) is a major type of persistent organic pollutants (POPs) that act as endocrine-disrupting chemicals. In the current study, we examined the mechanism underlying the effect of PCB-153 on glucose and lipid metabolism in vivo and in vitro. We found that PCB-153 induced per se and worsened high fat diet (HFD)-resulted increase of blood glucose level and glucose and insulin intolerance. In addition, PCB-153 induced per se and worsened HFD-resulted increase of triglyceride content and adipose mass. Moreover, PCB-153 concentration-dependently inhibited insulin-dependent glucose uptake and lipid accumulation in cultured hepatocytes and adipocytes. PCB-153 induced the expression and nuclear translocation of p65 NF-κB and the expression of its downstream inflammatory markers, and worsened HFD-resulted increase of those inflammatory markers. Inhibition of NF-κB significantly suppressed PCB-153-induced inflammation, lipid accumulation and decrease of glucose uptake. PCB-153 induced oxidative stress and decreased hepatocyte nuclear factor 1b (HNF1b) and glutathione peroxidase 1 (GPx1) expression in vivo and in vitro. Overexpression of HNF1b increased GPx1 expression, decreased ROS level, decreased Srebp1, ACC and FAS expression, and inhibited PCB-153-resulted oxidative stress, NF-κB-mediated inflammation, and final glucose/lipid metabolic disorder. Our results suggest that dysregulation of HNF1b/ROS/NF-κB plays an important role in PCB-153-induced glucose/lipid metabolic disorder.