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1.
Annu Rev Immunol ; 38: 79-98, 2020 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-31800327

RESUMEN

DNA has been known to be a potent immune stimulus for more than half a century. However, the underlying molecular mechanisms of DNA-triggered immune response have remained elusive until recent years. Cyclic GMP-AMP synthase (cGAS) is a major cytoplasmic DNA sensor in various types of cells that detect either invaded foreign DNA or aberrantly located self-DNA. Upon sensing of DNA, cGAS catalyzes the formation of cyclic GMP-AMP (cGAMP), which in turn activates the ER-localized adaptor protein MITA (also named STING) to elicit the innate immune response. The cGAS-MITA axis not only plays a central role in host defense against pathogen-derived DNA but also acts as a cellular stress response pathway by sensing aberrantly located self-DNA, which is linked to the pathogenesis of various human diseases. In this review, we summarize the spatial and temporal mechanisms of host defense to cytoplasmic DNA mediated by the cGAS-MITA axis and discuss the association of malfunctions of this axis with autoimmune and other diseases.


Asunto(s)
ADN/inmunología , Inmunidad Innata , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Biomarcadores , Citoplasma/inmunología , Citoplasma/metabolismo , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Evasión Inmune , Interferón Tipo I/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo
2.
Annu Rev Cell Dev Biol ; 34: 357-379, 2018 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-30095291

RESUMEN

Microbial nucleic acids are major signatures of invading pathogens, and their recognition by various host pattern recognition receptors (PRRs) represents the first step toward an efficient innate immune response to clear the pathogens. The nucleic acid-sensing PRRs are localized at the plasma membrane, the cytosol, and/or various cellular organelles. Sensing of nucleic acids and signaling by PRRs involve recruitment of distinct signaling components, and PRRs are intensively regulated by cellular organelle trafficking. PRR-mediated innate immune responses are also heavily regulated by posttranslational modifications, including phosphorylation, polyubiquitination, sumoylation, and glutamylation. In this review, we focus on our current understanding of recognition of microbial nucleic acid by PRRs, particularly on their regulation by organelle trafficking and posttranslational modifications. We also discuss how sensing of self nucleic acids and dysregulation of PRR-mediated signaling lead to serious human diseases.


Asunto(s)
Interacciones Huésped-Patógeno/genética , Inmunidad Innata/genética , Ácidos Nucleicos/genética , Receptores de Reconocimiento de Patrones/genética , Bacterias/genética , Bacterias/patogenicidad , Citoplasma/inmunología , Citoplasma/microbiología , ADN Bacteriano/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Ácidos Nucleicos/inmunología , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal/genética
3.
Nat Immunol ; 17(9): 1057-66, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27428826

RESUMEN

STING is a central adaptor in the innate immune response to DNA viruses. However, the manner in which STING activity is regulated remains unclear. We identified iRhom2 ('inactive rhomboid protein 2') as a positive regulator of DNA-virus-triggered induction of type I interferons. iRhom2 deficiency markedly impaired DNA-virus- and intracellular-DNA-induced signaling in cells, and iRhom2-deficient mice were more susceptible to lethal herpes simplex virus type 1 (HSV-1) infection. iRhom2 was constitutively associated with STING and acted in two distinct processes to regulate STING activity. iRhom2 recruited the translocon-associated protein TRAPß to the STING complex to facilitate trafficking of STING from the endoplasmic reticulum to perinuclear microsomes. iRhom2 also recruited the deubiquitination enzyme EIF3S5 to maintain the stability of STING through removal of its K48-linked polyubiquitin chains. These results suggest that iRhom2 is essential for STING activity, as it regulates TRAPß-mediated translocation and EIF3S5-mediated deubiquitination of STING.


Asunto(s)
Proteínas Portadoras/metabolismo , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Proteínas de la Membrana/metabolismo , Microsomas/metabolismo , Animales , Proteínas Portadoras/genética , Células Cultivadas , Factor 3 de Iniciación Eucariótica/metabolismo , Inmunidad Innata , Interferón Tipo I/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Estabilidad Proteica , Transporte de Proteínas/genética , Fosfatasa Ácida Tartratorresistente/metabolismo , Ubiquitinación
4.
Nat Immunol ; 17(3): 241-9, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26692175

RESUMEN

The gene encoding PTEN is one of the most frequently mutated tumor suppressor-encoding genes in human cancer. While PTEN's function in tumor suppression is well established, its relationship to anti-microbial immunity remains unknown. Here we found a pivotal role for PTEN in the induction of type I interferon, the hallmark of antiviral innate immunity, that was independent of the pathway of the kinases PI(3)K and Akt. PTEN controlled the import of IRF3, a master transcription factor responsible for IFN-ß production, into the nucleus. We further identified a PTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity of PTEN was essential for the activation of IRF3 and its import into the nucleus. Our study identifies crosstalk between PTEN and IRF3 in tumor suppression and innate immunity.


Asunto(s)
Inmunidad Innata/inmunología , Factor 3 Regulador del Interferón/inmunología , Interferón Tipo I/inmunología , Fosfohidrolasa PTEN/inmunología , Infecciones por Respirovirus/inmunología , Infecciones por Rhabdoviridae/inmunología , Animales , Línea Celular , Línea Celular Tumoral , Núcleo Celular , Proliferación Celular , Citocinas/inmunología , Células Dendríticas/inmunología , Electroforesis en Gel de Poliacrilamida , Técnica del Anticuerpo Fluorescente , Técnicas de Transferencia de Gen , Células HEK293 , Humanos , Immunoblotting , Inmunoprecipitación , Factor 3 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/genética , Células MCF-7 , Macrófagos/inmunología , Espectrometría de Masas , Ratones , Microscopía Confocal , Mutagénesis Sitio-Dirigida , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Virus Sendai , Vesiculovirus
5.
Immunity ; 49(3): 438-448.e5, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30193849

RESUMEN

Recognition of viral RNA by the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiates innate antiviral immune response. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified ZCCHC3 as a positive regulator of the RLRs including RIG-I and MDA5. ZCCHC3 deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and ZCCHC3-deficient mice were more susceptible to RNA virus infection. ZCCHC3 was associated with RIG-I and MDA5 and functions in two distinct processes for regulation of RIG-I and MDA5 activities. ZCCHC3 bound to dsRNA and enhanced the binding of RIG-I and MDA5 to dsRNA. ZCCHC3 also recruited the E3 ubiquitin ligase TRIM25 to the RIG-I and MDA5 complexes to facilitate its K63-linked polyubiquitination and activation. Thus, ZCCHC3 is a co-receptor for RIG-I and MDA5, which is critical for RLR-mediated innate immune response to RNA virus.


Asunto(s)
Proteína 58 DEAD Box/metabolismo , Infecciones por Virus ARN/inmunología , Virus ARN/fisiología , ARN Viral/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas de Unión al ADN/metabolismo , Regulación Viral de la Expresión Génica , Células HEK293 , Humanos , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , ARN Viral/inmunología , Proteínas de Unión al ARN/genética , Células THP-1 , Factores de Transcripción/metabolismo , Ubiquitinación
6.
Immunity ; 45(3): 555-569, 2016 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-27637147

RESUMEN

During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation. Trim38 also sumoylated Sting during the early phase of viral infection, promoting both Sting activation and protein stability. In the late phase of infection, cGas and Sting were desumoylated by Senp2 and subsequently degraded via proteasomal and chaperone-mediated autophagy pathways, respectively. Our findings reveal an essential role for Trim38 in the innate immune response to DNA virus and provide insight into the mechanisms that ensure optimal activation and deactivation of the cGAS-STING pathway.


Asunto(s)
Virus ADN/inmunología , ADN/metabolismo , Nucleótidos Cíclicos/metabolismo , Nucleotidiltransferasas/metabolismo , Sumoilación/fisiología , Virosis/metabolismo , Animales , Proteínas Portadoras/metabolismo , Cisteína Endopeptidasas/metabolismo , Inmunidad Innata/inmunología , Cinética , Proteínas de la Membrana/metabolismo , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Transducción de Señal/inmunología , Transducción de Señal/fisiología , Sumoilación/inmunología , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Ubiquitinación/inmunología , Ubiquitinación/fisiología
7.
Proc Natl Acad Sci U S A ; 119(10): e2116279119, 2022 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-35238669

RESUMEN

The warning cytokine interleukin-33 receptor (IL-33R) mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases such as pulmonary fibrosis and rheumatoid arthritis. Whether and how IL-33R is regulated remain enigmatic. Here, we identified ubiquitin-specific protease 38 (USP38) as a negative regulator of IL-33R­mediated signaling. USP38 deficiency promotes interleukin-33 (IL-33)­induced downstream proinflammatory responses in vitro and in vivo. Usp38−/− mice are more susceptible to inflammatory damage and death and developed more serious pulmonary fibrosis after bleomycin treatment. USP38 is constitutively associated with IL-33R and deconjugates its K27-linked polyubiquitination at K511, resulting in its autophagic degradation. We further show that the E3 ubiquitin ligase tumor necrosis factor receptor­associated factor 6 (TRAF6) catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33­mediated signaling. Our findings suggest that K27-linked polyubiquitination and deubiquitination of IL-33R by TRAF6 and USP38 reciprocally regulate IL-33R level and signaling, which represents a critical mechanism in the regulation of IL-33­triggered lung inflammatory response and pulmonary fibrosis.


Asunto(s)
Inflamación/fisiopatología , Interleucina-33/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fibrosis Pulmonar/fisiopatología , Proteasas Ubiquitina-Específicas/metabolismo , Autofagia , Regulación hacia Abajo , Humanos , Inflamación/metabolismo , Interleucina-33/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Transducción de Señal , Proteasas Ubiquitina-Específicas/genética , Ubiquitinación
8.
Proc Natl Acad Sci U S A ; 119(43): e2207280119, 2022 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-36252040

RESUMEN

The current view of nucleic acid-mediated innate immunity is that binding of intracellular sensors to nucleic acids is sufficient for their activation. Here, we report that endocytosis of virus or foreign DNA initiates a priming signal for the DNA sensor cyclic GMP-AMP synthase (cGAS)-mediated innate immune response. Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. Upon binding to DNA, the primed cGAS initiates robust cGAMP production and mediator of IRF3 activation/stimulator of interferon genes-dependent innate immune response. Consistently, blocking the V-ATPase-SYK axis impairs DNA virus- and transfected DNA-induced cGAMP production and expression of antiviral genes. Our findings reveal that V-ATPase-SYK-mediated tyrosine phosphorylation of cGAS following endocytosis of virus or other cargos serves as a priming signal for cGAS activation and innate immune response.


Asunto(s)
Endocitosis , Inmunidad Innata , Nucleotidiltransferasas , Quinasa Syk , ATPasas de Translocación de Protón Vacuolares , Animales , Humanos , Ratones , ADN , Interferones/metabolismo , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Transducción de Señal/genética , Quinasa Syk/metabolismo , Tirosina , ATPasas de Translocación de Protón Vacuolares/metabolismo
9.
Immunity ; 41(6): 871-3, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25526298

RESUMEN

STING (also known as MITA) is a central component in innate immunity against DNA virus. In this issue of Immunity, Wang et al. (2014) demonstrate that K27-linked polyubiquitination of STING (MITA) by the ER-associated E3 ligase AMFR is essential for STING (MITA)-mediated signaling and innate antiviral response.


Asunto(s)
Retículo Endoplásmico/metabolismo , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Microsomas/metabolismo , Células Mieloides/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores del Factor Autocrino de Motilidad/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales
10.
Immunity ; 40(3): 329-41, 2014 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-24560620

RESUMEN

Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3(-/-) mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP.


Asunto(s)
ADN/inmunología , Inmunidad Innata , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Animales , Línea Celular , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacología , Citocinas/biosíntesis , Herpes Simple/inmunología , Herpes Simple/metabolismo , Herpesvirus Humano 1/fisiología , Humanos , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Interferón Tipo I/biosíntesis , Ratones , Ratones Noqueados , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas
11.
Proc Natl Acad Sci U S A ; 117(35): 21568-21575, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32817552

RESUMEN

The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA-triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus-induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus.


Asunto(s)
Infecciones por Virus ADN/inmunología , Virus ADN/inmunología , Lisina Acetiltransferasa 5/inmunología , Nucleotidiltransferasas/inmunología , Acetilación , Animales , GMP Cíclico/metabolismo , Infecciones por Virus ADN/genética , Infecciones por Virus ADN/metabolismo , Virus ADN/genética , Femenino , Células HEK293 , Células HeLa , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Interferón beta/inmunología , Lisina Acetiltransferasa 5/genética , Lisina Acetiltransferasa 5/metabolismo , Masculino , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Procesamiento Proteico-Postraduccional , Transducción de Señal , Proteínas Virales/metabolismo
12.
PLoS Pathog ; 16(4): e1008457, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32251420

RESUMEN

The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5), sense cytoplasmic viral RNA and initiate innate antiviral responses. How RIG-I and MDA5 are differentially regulated remains enigmatic. In this study, we identified the guanylate-binding protein (GBP) and zinc-finger FYVE domain-containing protein ZFYVE1 as a negative regulator of MDA5- but not RIG-I-mediated innate antiviral responses. ZFYVE1-deficiency promoted MDA5- but not RIG-I-mediated transcription of downstream antiviral genes. Comparing to wild-type mice, Zfyve1-/- mice were significantly protected from lethality induced by encephalomyocarditis virus (EMCV) that is sensed by MDA5, whereas Zfyve1-/- and Zfyve1+/+ mice were comparable to death induced by vesicular stomatitis virus (VSV) that is sensed by RIG-I. Mechanistically, ZFYVE1 interacted with MDA5 but not RIG-I. ZFYVE1 bound to viral RNA and decreased the ligand binding and oligomerization of MDA5. These findings suggest that ZFYVE1 acts as a specific negative regulator of MDA5-mediated innate immune responses by inhibiting its ligand binding and oligomerization.


Asunto(s)
Infecciones por Cardiovirus/inmunología , Proteína 58 DEAD Box/inmunología , Virus de la Encefalomiocarditis/fisiología , Helicasa Inducida por Interferón IFIH1/inmunología , Proteínas de la Membrana/inmunología , Animales , Infecciones por Cardiovirus/genética , Infecciones por Cardiovirus/virología , Proteína 58 DEAD Box/genética , Virus de la Encefalomiocarditis/genética , Humanos , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
13.
Proc Natl Acad Sci U S A ; 116(40): 20063-20069, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31527250

RESUMEN

Upon cytosolic viral DNA stimulation, cGMP-AMP synthase (cGAS) catalyzes synthesis of 2'3'cGMP-AMP (cGAMP), which binds to the adaptor protein MITA (mediator of IRF3 activation, also called STING, stimulator of IFN genes) and induces innate antiviral response. How the activity of MITA/STING is regulated to avoid excessive innate immune response is not fully understood. Here we identified the tyrosine-protein phosphatase nonreceptor type (PTPN) 1 and 2 as MITA/STING-associated proteins. PTPN1 and PTPN2 are associated with MITA/STING following viral infection and dephosphorylate MITA/STING at Y245. Dephosphorylation of MITA/STING leads to its degradation via the ubiquitin-independent 20S proteasomal pathway, which is dependent on the intrinsically disordered region (IDR) of MITA/STING. Deficiencies of PTPN1 and PTPN2 enhance viral DNA-induced transcription of downstream antiviral genes and innate antiviral response. Our findings reveal that PTPN1/2-mediated dephosphorylation of MITA/STING and its degradation by the 20S proteasomal pathway is an important regulatory mechanism of innate immune response to DNA virus.


Asunto(s)
Inmunidad Innata , Proteínas de la Membrana/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Virosis/inmunología , Virosis/metabolismo , Animales , Biomarcadores , ADN Viral/genética , ADN Viral/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunohistoquímica , Ratones , Fosforilación , Unión Proteica , Proteolisis , Transducción de Señal , Virosis/virología
14.
Proc Natl Acad Sci U S A ; 116(21): 10447-10452, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-31061131

RESUMEN

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.


Asunto(s)
Carcinogénesis/metabolismo , Colitis/metabolismo , Factor de Transcripción STAT3/metabolismo , Células Th17 , Animales , Diferenciación Celular , Colitis/complicaciones , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Ratones
15.
J Immunol ; 203(1): 259-268, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31127032

RESUMEN

The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-ß-activated kinase 1 (TAK1)-mediated NF-κB activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-α- and IL-1ß-triggered NF-κB activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF-α- and IL-1ß-triggered NF-κB activation and transcription of downstream genes, whereas USP19 deficiency had the opposite effects. Usp19-/- mice produced higher levels of inflammatory cytokines and were more susceptible to TNF-α- and IL-1ß-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-α- or IL-1ß-dependent manner and specifically deconjugated K63- and K27-linked polyubiquitin chains from TAK1, leading to the impairment of TAK1 activity and the disruption of the TAK1-TAB2/3 complex. Our findings provide new insights to the complicated molecular mechanisms of the attenuation of the inflammatory response.


Asunto(s)
Endopeptidasas/metabolismo , Inflamación/inmunología , Quinasas Quinasa Quinasa PAM/metabolismo , FN-kappa B/metabolismo , Sepsis/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Susceptibilidad a Enfermedades , Endopeptidasas/genética , Células HEK293 , Humanos , Tolerancia Inmunológica , Interleucina-1beta/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , ARN Interferente Pequeño/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitinación
16.
Proc Natl Acad Sci U S A ; 115(49): 12483-12488, 2018 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-30442668

RESUMEN

The proinflammatory cytokine IL-1ß plays critical roles in inflammatory and autoimmune diseases. IL-1ß signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1ß-triggered signaling. Overexpression of MARCH3 inhibited IL-1ß-triggered activation of NF-κB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1ß injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1ß stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3-mediated IL-1RI degradation is an important mechanism for attenuating IL-1ß-triggered inflammatory response.


Asunto(s)
Inflamación/metabolismo , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Listeriosis/patología , Receptores Tipo I de Interleucina-1/metabolismo , Animales , Regulación de la Expresión Génica , Interleucina-1beta/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Listeria monocytogenes , Ratones , Ratones Noqueados , Fosforilación , Receptores Tipo I de Interleucina-1/genética , Tirosina , Ubiquitinación
17.
Biochem Biophys Res Commun ; 526(1): 199-205, 2020 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-32201077

RESUMEN

Upon detection of viral DNA, the cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) utilizes GTP and ATP as substrates to synthesize the second messenger molecule 2'3'cyclic GMP-AMP (cGAMP), which binds to the ER-associated adaptor protein MITA/STING to signal innate antiviral response to DNA virus. How the cGAS-MITA pathways are post-translationally regulated is not fully understood. In this study, we identified the tyrosine kinase CSK as a positive regulator of cGAS-MITA mediated innate antiviral response. CSK-deficiency inhibits DNA virus-triggered induction of downstream antiviral effector genes. Following DNA virus infection, CSK phosphorylates MITA at Y240 and Y245, which is important for its activation. These results suggest that CSK plays a role in modulating innate immune response to DNA virus.


Asunto(s)
Proteína Tirosina Quinasa CSK/metabolismo , Virus ADN/inmunología , Inmunidad Innata , Proteínas de la Membrana/metabolismo , Animales , Proteína Tirosina Quinasa CSK/deficiencia , Línea Celular , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación
18.
PLoS Pathog ; 14(10): e1007336, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30321235

RESUMEN

MITA (also called STING) is a central adaptor protein in innate immune response to cytosolic DNA. Cellular trafficking of MITA from the ER to perinuclear microsomes after DNA virus infection is critical for MITA activation and onset of innate antiviral response. Here we found that SNX8 is a component of DNA-triggered induction of downstream effector genes and innate immune response. Snx8-/- mice infected with the DNA virus HSV-1 exhibited lower serum cytokine levels and higher viral titers in the brains, resulting in higher lethality. Mechanistically, SNX8 recruited the class III phosphatylinositol 3-kinase VPS34 to MITA, which is required for trafficking of MITA from the ER to perinuclear microsomes. Our findings suggest that SNX8 is a critical component in innate immune response to cytosolic DNA and DNA virus.


Asunto(s)
Encéfalo/inmunología , Infecciones por Virus ADN/inmunología , Virus ADN/patogenicidad , Inmunidad Innata/inmunología , Proteínas de la Membrana/metabolismo , Nexinas de Clasificación/fisiología , Animales , Encéfalo/patología , Encéfalo/virología , Citocinas/metabolismo , Infecciones por Virus ADN/metabolismo , Infecciones por Virus ADN/virología , Virus ADN/inmunología , Células HEK293 , Células HeLa , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transporte de Proteínas , Carga Viral
19.
Proc Natl Acad Sci U S A ; 114(49): 13000-13005, 2017 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-29180417

RESUMEN

IFNγ is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNγ also activates an IKKß-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNγ-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNγ-triggered noncanonical signaling pathway. SNX8-deficiency impaired IFNγ-triggered induction of a subset of downstream genes. Snx8-/- mice infected with Listeria monocytogenes exhibited lower serum cytokine levels and higher bacterial loads in the livers and spleens, resulting in higher lethality. Mechanistically, SNX8 interacted with JAK1 and IKKß and promoted their association. IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKß to the JAK1 complex. SNX8-deficiency impaired IFNγ-induced oligomerization and autophosphorylation of IKKß at Ser177, which is critical for selective induction of downstream genes. Our findings suggest that SNX8 acts as a link for IFNγ-triggered noncanonical signaling pathway, which induces a subset of downstream genes important for host defense against L. monocytogenes infection.


Asunto(s)
Quinasa I-kappa B/inmunología , Janus Quinasa 1/inmunología , Listeria monocytogenes/patogenicidad , Listeriosis/genética , Nexinas de Clasificación/inmunología , Animales , Carga Bacteriana , Regulación de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Quinasa I-kappa B/deficiencia , Quinasa I-kappa B/genética , Interferón gamma/genética , Interferón gamma/inmunología , Janus Quinasa 1/genética , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Listeriosis/microbiología , Listeriosis/mortalidad , Hígado/inmunología , Hígado/microbiología , Ratones , Ratones Noqueados , Peptidoglicano/administración & dosificación , Fosforilación , Transducción de Señal , Nexinas de Clasificación/deficiencia , Nexinas de Clasificación/genética , Bazo/inmunología , Bazo/microbiología , Análisis de Supervivencia , Células THP-1
20.
Biochem Biophys Res Commun ; 508(3): 667-674, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30527812

RESUMEN

Virus-induced signaling adaptor (VISA), which mediates the production of type I interferon, is crucial for the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Upon viral infection, RIG-I recognizes double-stranded viral RNA and interacts with VISA to mediate antiviral innate immunity. However, the mechanisms underlying RIG/VISA-mediated antiviral regulation remain unclear. In this study, we confirmed that receptor for activated C kinase 1 (RACK1) interacts with VISA and attenuates the RIG/VISA-mediated antiviral innate immune signaling pathway. Overexpression of RACK1 inhibited the interferon-ß (IFN-ß) promoter; interferon-stimulated response element (ISRE); nuclear factor kappa B (NF-κB) activation; and dimerization of interferon regulatory factor 3 (IRF3) mediated by RIG-I, VISA, and TANK-binding kinase 1 (TBK1). A reduction in RACK1 expression level upon small interfering RNA knockdown increased RIG/VISA-mediated antiviral transduction. Additionally, RACK1 disrupted formation of the VISA-tumor necrosis factor receptor-associated factor 2 (TRAF2), VISA-TRAF3, and VISA-TRAF6 complexes during RIG-I/VISA-mediated signal transduction. Additionally, RACK1 enhanced K48-linked ubiquitination of VISA, attenuated its K63-linked ubiquitination, and decreased VISA-mediated antiviral signal transduction. Together, these results indicate that RACK1 interacts with VISA to repress downstream signaling and downregulates virus-induced IFN-ß production in the RIG-I/VISA signaling pathway.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antivirales/metabolismo , Proteína 58 DEAD Box/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Cinasa C Activada/metabolismo , Transducción de Señal , Técnicas de Silenciamiento del Gen , Humanos , Interferón beta/biosíntesis , Interferón beta/metabolismo , Lisina/metabolismo , Complejos Multiproteicos/metabolismo , Regiones Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Interferente Pequeño/metabolismo , Virus Sendai/fisiología , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Ubiquitinación
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