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1.
Mol Cell ; 82(23): 4519-4536.e7, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36384137

RESUMO

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.


Assuntos
Proteínas Quinases Ativadas por AMP , Ácidos Nucleicos , Animais , Proteínas Quinases Ativadas por AMP/genética , Imunidade Inata , Antivirais , Glucose
2.
Mol Cell ; 81(1): 198-211.e6, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33296677

RESUMO

Replication fork reversal is a global response to replication stress in mammalian cells, but precisely how it occurs remains poorly understood. Here, we show that, upon replication stress, DNA topoisomerase IIalpha (TOP2A) is recruited to stalled forks in a manner dependent on the SNF2-family DNA translocases HLTF, ZRANB3, and SMARCAL1. This is accompanied by an increase in TOP2A SUMOylation mediated by the SUMO E3 ligase ZATT and followed by recruitment of a SUMO-targeted DNA translocase, PICH. Disruption of the ZATT-TOP2A-PICH axis results in accumulation of partially reversed forks and enhanced genome instability. These results suggest that fork reversal occurs via a sequential two-step process. First, HLTF, ZRANB3, and SMARCAL1 initiate limited fork reversal, creating superhelical strain in the newly replicated sister chromatids. Second, TOP2A drives extensive fork reversal by resolving the resulting topological barriers and via its role in recruiting PICH to stalled forks.


Assuntos
DNA Helicases/metabolismo , Replicação do DNA , DNA Topoisomerases Tipo II/metabolismo , Genoma Humano , Instabilidade Genômica , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , DNA Helicases/genética , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Células HeLa , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Mol Cell ; 81(20): 4147-4164.e7, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34453890

RESUMO

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.


Assuntos
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 Sinais
4.
Mol Cell ; 80(5): 810-827.e7, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33171123

RESUMO

Mitochondrial morphology shifts rapidly to manage cellular metabolism, organelle integrity, and cell fate. It remains unknown whether innate nucleic acid sensing, the central and general mechanisms of monitoring both microbial invasion and cellular damage, can reprogram and govern mitochondrial dynamics and function. Here, we unexpectedly observed that upon activation of RIG-I-like receptor (RLR)-MAVS signaling, TBK1 directly phosphorylated DRP1/DNM1L, which disabled DRP1, preventing its high-order oligomerization and mitochondrial fragmentation function. The TBK1-DRP1 axis was essential for assembly of large MAVS aggregates and healthy antiviral immunity and underlay nutrient-triggered mitochondrial dynamics and cell fate determination. Knockin (KI) strategies mimicking TBK1-DRP1 signaling produced dominant-negative phenotypes reminiscent of human DRP1 inborn mutations, while interrupting the TBK1-DRP1 connection compromised antiviral responses. Thus, our findings establish an unrecognized function of innate immunity governing both morphology and physiology of a major organelle, identify a lacking loop during innate RNA sensing, and report an elegant mechanism of shaping mitochondrial dynamics.


Assuntos
Dinaminas/metabolismo , Mitocôndrias/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA/metabolismo , Peixe-Zebra/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Dinaminas/genética , Células HCT116 , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Proteínas Serina-Treonina Quinases/genética , RNA/genética , Transdução de Sinais/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
EMBO J ; 42(4): e111549, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36598329

RESUMO

YAP/TAZ transcriptional co-activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST-LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCFß-TrCP . When the MST-LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate TEAD-dependent gene transcription. Hippo signaling-independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to ß-TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias da Mama , Humanos , Feminino , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transativadores/genética , Transativadores/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Sinalização YAP , Proteínas Contendo Repetições de beta-Transducina/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Ubiquitinação , Neoplasias da Mama/genética , Ubiquitinas/metabolismo , Ligases/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo
6.
J Biol Chem ; 299(5): 104668, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37011862

RESUMO

Inhibition of heat shock protein 90 (Hsp90), a prominent molecular chaperone, effectively limits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but little is known about any interaction between Hsp90 and SARS-CoV-2 proteins. Here, we systematically analyzed the effects of the chaperone isoforms Hsp90α and Hsp90ß on individual SARS-CoV-2 viral proteins. Five SARS-CoV-2 proteins, namely nucleocapsid (N), membrane (M), and accessory proteins Orf3, Orf7a, and Orf7b were found to be novel clients of Hsp90ß in particular. Pharmacological inhibition of Hsp90 with 17-DMAG results in N protein proteasome-dependent degradation. Hsp90 depletion-induced N protein degradation is independent of CHIP, a ubiquitin E3 ligase previously identified for Hsp90 client proteins, but alleviated by FBXO10, an E3 ligase identified by subsequent siRNA screening. We also provide evidence that Hsp90 depletion may suppress SARS-CoV-2 assembly partially through induced M or N degradation. Additionally, we found that GSDMD-mediated pyroptotic cell death triggered by SARS-CoV-2 was mitigated by inhibition of Hsp90. These findings collectively highlight a beneficial role for targeting of Hsp90 during SARS-CoV-2 infection, directly inhibiting virion production and reducing inflammatory injury by preventing the pyroptosis that contributes to severe SARS-CoV-2 disease.


Assuntos
COVID-19 , Proteínas de Choque Térmico HSP90 , Piroptose , SARS-CoV-2 , Vírion , Humanos , COVID-19/patologia , COVID-19/fisiopatologia , COVID-19/virologia , Proteínas de Choque Térmico HSP90/metabolismo , SARS-CoV-2/química , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Ubiquitina-Proteína Ligases/metabolismo , Vírion/química , Vírion/crescimento & desenvolvimento , Vírion/metabolismo , Proteínas Virais/metabolismo
7.
Eur J Immunol ; 53(9): e2350386, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37424054

RESUMO

Cyclic GMP-AMP synthase (cGAS) monitors dsDNA in the cytosol in response to pathogenic invasion or tissue injury, initiating cGAS-STING signaling cascades that regulate various cellular physiologies, including IFN /cytokine production, autophagy, protein synthesis, metabolism, senescence, and distinct types of cell death. cGAS-STING signaling is crucial for host defense and tissue homeostasis; however, its dysfunction frequently leads to infectious, autoimmune, inflammatory, degenerative, and cancerous diseases. Our knowledge regarding the relationships between cGAS-STING signaling and cell death is rapidly evolving, highlighting their essential roles in pathogenesis and disease progression. Nevertheless, the direct control of cell death by cGAS-STING signaling, rather than IFN/NF-κB-mediated transcriptional regulation, remains relatively unexplored. This review examines the mechanistic interplays between cGAS-STING cascades and apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic/lysosomal cell death. We will also discuss their pathological implications in human diseases, particularly in autoimmunity, cancer, and organ injury scenarios. We hope that this summary will stimulate discussion for further exploration of the complex life-or-death responses to cellular damage mediated by cGAS-STING signaling.


Assuntos
Nucleotidiltransferases , Transdução de Sinais , Humanos , Transdução de Sinais/fisiologia , DNA/metabolismo , Apoptose
8.
PLoS Biol ; 19(2): e3001122, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33630828

RESUMO

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.


Assuntos
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 YAP
9.
Genes Dev ; 30(9): 1086-100, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27125670

RESUMO

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.


Assuntos
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/imunologia
10.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 35-46, 2024 Jan 19.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-38426691

RESUMO

Innate nucleic acid sensing is a ubiquitous and highly conserved immunological process, which is pivotal for monitoring and responding to pathogenic invasion and cellular damage, and central to host defense, autoimmunity, cell fate determination and tumorigenesis. Tyrosine phosphorylation, a major type of post-translational modification, plays a critical regulatory role in innate immune sensing pathway. Core members of nucleic acid sensing signaling pathway, such as cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), stimulator of interferon genes (STING), and TANK binding kinase 1 (TBK1), are all subject to activity regulation triggered by tyrosine phosphorylation, thereby affecting the host antiviral defense and anti-tumor immunity under physiological or pathological conditions. This review summarizes the recent advances in research on tyrosine kinases and tyrosine phosphorylation in regulation of nucleic acid sensing. The function and potential applications of targeting tyrosine phosphorylation in anti-tumor immunity is disussed to provide insights for understanding and expanding new anti-tumor strategies.


Assuntos
Ácidos Nucleicos , Proteínas Tirosina Quinases , Imunidade Inata , Transdução de Sinais , Tirosina
11.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 1-14, 2024 Jan 05.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-38229501

RESUMO

Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mitochondrial reactive oxygen species, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.


Assuntos
Carcinogênese , Mitocôndrias , Humanos , Diferenciação Celular , DNA Mitocondrial , Transdução de Sinais , Microambiente Tumoral
12.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 15-24, 2024 Jan 12.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-38229499

RESUMO

Targeting cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is a promising strategy for tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of a second messenger 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhances the immune surveillance and inflammatory responses. The membrane proteins, including a specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. The ligand-receptor interactions for interferon transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment, explores how these mechanisms modulate immunological processes and discusses potential interventions and immunotherapeutic strategies targeting these signaling cascades.


Assuntos
Comunicação Celular , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal , Citocinas , Interferons
13.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 25-34, 2024 Jan 26.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-38273467

RESUMO

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalyzes the formation of a second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type Ⅰ interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, is also a significant contributor to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type Ⅰ interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type Ⅰ interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.


Assuntos
Interferon Tipo I , NF-kappa B , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , DNA , Carcinogênese , Microambiente Tumoral
14.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 64-72, 2024 Jan 19.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-38426692

RESUMO

Hepatocellular carcinoma (HCC) is a serious neoplastic disease with increasing incidence and mortality, accounting for 90% of all liver cancers. Hepatitis viruses are the major causative agents in the development of HCC. Hepatitis A virus (HAV) primarily causes acute infections, which is associated with HCC to a certain extent, as shown by clinicopathological studies. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections lead to persistent liver inflammation and cirrhosis, disrupt multiple pathways associated with cellular apoptosis and proliferation, and are the most common viral precursors of HCC. Mutations in the HBV X protein (HBx) gene are closely associated with the incidence of HCC, while the expression of HCV core proteins contributes to hepatocellular lipid accumulation, thereby promoting tumorigenesis. In the clinical setting, hepatitis D virus (HDV) frequently co-infects with HBV, increasing the risk of chronic hepatitis. Hepatitis E virus (HEV) usually causes acute infections. However, chronic infections of HEV have been increasing recently, particularly in immuno-compromised patients and organ transplant recipients, which may increase the risk of progression to cirrhosis and the occurrence of HCC. Early detection, effective intervention and vaccination against these viruses may significantly reduce the incidence of liver cancer, while mechanistic insights into the interplay between hepatitis viruses and HCC may facilitate the development of more effective intervention strategies. This article provides a comprehensive overview of hepatitis viruses and reviews recent advances in research on aberrant hepatic immune responses and the pathogenesis of HCC due to viral infection.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Hepatite B , Hepatite C , Hepatite Viral Humana , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/genética , Hepatite B Crônica/complicações , Hepatite B/complicações , Hepatite Viral Humana/complicações , Hepatite C/complicações , Cirrose Hepática/complicações
15.
J Hepatol ; 78(4): 704-716, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36574921

RESUMO

BACKGROUND & AIMS: Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action. METHODS: Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase. RESULTS: We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage. CONCLUSIONS: In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals. IMPACT AND IMPLICATIONS: Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development.


Assuntos
Vírus da Hepatite E , Hepatite E , Animais , Humanos , Feminino , Gravidez , Proteostase , Proteínas do Complexo da Replicase Viral , Hepatite E/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Proteínas Virais , Replicação Viral
16.
EMBO J ; 38(14): e99945, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304624

RESUMO

TGF-ß controls a variety of cellular functions during development. Abnormal TGF-ß responses are commonly found in human diseases such as cancer, suggesting that TGF-ß signaling must be tightly regulated. Here, we report that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates TGF-ß signaling independent of its phosphatase activity. PTPN3 stabilizes TGF-ß type I receptor (TßRI) through attenuating the interaction between Smurf2 and TßRI. Consequently, PTPN3 facilitates TGF-ß-induced R-Smad phosphorylation, transcriptional responses, and subsequent physiological responses. Importantly, the leucine-to-arginine substitution at amino acid residue 232 (L232R) of PTPN3, a frequent mutation found in intrahepatic cholangiocarcinoma (ICC), disables its role in enhancing TGF-ß signaling and abolishes its tumor-suppressive function. Our findings have revealed a vital role of PTPN3 in regulating TGF-ß signaling during normal physiology and pathogenesis.


Assuntos
Neoplasias Hepáticas/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 3/genética , Proteína Tirosina Fosfatase não Receptora Tipo 3/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Substituição de Aminoácidos , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Transplante de Neoplasias , Fosforilação , Estabilidade Proteica , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Proteínas Smad/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
17.
Development ; 147(22)2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33060129

RESUMO

Adherens junction remodeling regulated by apical polarity proteins constitutes a major driving force for tissue morphogenesis, although the precise mechanism remains inconclusive. Here, we report that, in zebrafish, the Crumbs complex component MPP5a interacts with small GTPase Rab11 in Golgi to transport cadherin and Crumbs components synergistically to the apical domain, thus establishing apical epithelial polarity and adherens junctions. In contrast, Par complex recruited by MPP5a is incapable of interacting with Rab11 but might assemble cytoskeleton to facilitate cadherin exocytosis. In accordance, dysfunction of MPP5a induces an invasive migration of epithelial cells. This adherens junction remodeling pattern is frequently observed in zebrafish lens epithelial cells and neuroepithelial cells. The data identify an unrecognized MPP5a-Rab11 complex and describe its essential role in guiding apical polarization and zonula adherens formation in epithelial cells.


Assuntos
Junções Aderentes/metabolismo , Movimento Celular/fisiologia , Polaridade Celular/fisiologia , Guanilato Ciclase/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Proteínas rab de Ligação ao GTP/metabolismo , Junções Aderentes/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Células Epiteliais , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Guanilato Ciclase/genética , Transporte Proteico/fisiologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas rab de Ligação ao GTP/genética
18.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 73-83, 2023 Feb 19.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-38413217

RESUMO

As the understanding of the pathogenic mechanisms of gastric cancer deepens and the identification of gastric cancer driver genes advances, drugs targeting gastric cancer driver genes have been applied in clinical practice. Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed human epidermal growth factor receptor 2 (HER2). Trastuzumab has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting vascular endothelial growth factor receptor 2 (VEGFR2) and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed fibroblast growth factor receptor 2 (FGFR2), while zolbetuximab targets overexpressed claudin 18.2 (CLDN18.2), significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer, and the treatment strategies for gastric cancer primarily based on targeting HER2, VEGF, FGFR2, CLDN18.2 and MET. This provides a reference for clinical application of targeted therapy for gastric cancer.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Fator A de Crescimento do Endotélio Vascular , Trastuzumab/uso terapêutico , Receptor ErbB-2 , Ramucirumab , Terapia de Alvo Molecular , Claudinas/uso terapêutico
19.
Mol Cell ; 56(6): 723-37, 2014 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-25526531

RESUMO

TGF-ß signaling is essential in many processes, including immune surveillance, and its dysregulation controls various diseases, including cancer, fibrosis, and inflammation. Studying the innate host defense, which functions in most cell types, we found that RLR signaling represses TGF-ß responses. This regulation is mediated by activated IRF3, using a dual mechanism of IRF3-directed suppression. Activated IRF3 interacts with Smad3, thus inhibiting TGF-ß-induced Smad3 activation and, in the nucleus, disrupts functional Smad3 transcription complexes by competing with coregulators. Consequently, IRF3 activation by innate antiviral signaling represses TGF-ß-induced growth inhibition, gene regulation and epithelial-mesenchymal transition, and the generation of Treg effector lymphocytes from naive CD4(+) lymphocytes. Conversely, silencing IRF3 expression enhances epithelial-mesenchymal transition, TGF-ß-induced Treg cell differentiation upon virus infection, and Treg cell generation in vivo. We present a mechanism of regulation of TGF-ß signaling by the antiviral defense, with evidence for its role in immune tolerance and cancer cell behavior.


Assuntos
Fator Regulador 3 de Interferon/fisiologia , Vírus Sendai/imunologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Animais , Diferenciação Celular , Transição Epitelial-Mesenquimal , Células HEK293 , Células Hep G2 , Humanos , Imunidade Inata , Camundongos Endogâmicos C57BL , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Transcrição Gênica , Ativação Transcricional/imunologia
20.
EMBO Rep ; 20(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30979708

RESUMO

Type I interferon (IFN)-induced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling drives the expression of IFN-stimulated genes (ISGs) to mediate antiviral response. The strength and duration of JAK-STAT signaling are tightly regulated to ensure effective antiviral defense while avoiding pathological inflammation and autoimmunity. Here, we report that cTAZ, an isoform of the Hippo pathway effector TAZ, is transcribed by an alternative promoter. Although majority of C-terminal sequences of TAZ is retained, cTAZ is not regulated by the Hippo signaling and does not mediate its growth-inhibitory functions. Instead, cTAZ negatively regulates JAK-STAT signaling by inhibiting STAT1/2 nuclear localization and ISG expression, and its expression is induced by type I IFN Thus, cTAZ functions as a modulator of JAK-STAT signaling and may play a role in fine-tuning cellular antiviral response.


Assuntos
Janus Quinases/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Transativadores/genética , Transcrição Gênica , Animais , Perfilação da Expressão Gênica , Via de Sinalização Hippo , Humanos , Camundongos , Modelos Biológicos , Fosforilação , Ligação Proteica , Multimerização Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , Isoformas de RNA , Fatores de Transcrição STAT/química , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
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