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1.
Mol Biol Rep ; 46(1): 1369-1375, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30628021

RESUMO

The activity and close regulation of nuclear factor kappaB (NF-κB) transcription factors is critical for a variety of cellular processes including inflammation, immunity, differentiation and cell survival. Thus, dysregulation of the NF-κB system could lead to serious diseases, e.g. uncoordinated growth of the normal tissue during the development of cancer. Transcriptional activity of the NF-κB factor RelA is regulated by a number of mechanisms which comprise ubiquitinylation by a multimeric ubiquitin ligase containing Elongins B and C, cullin-2 (Cul2) and suppressor of cytokine signaling 1 (SOCS1), but also USP48-dependent deubiquitinylation. Further, USP48 promotes cell survival and antagonizes also other E3 ligase functions which are involved in genome stability and DNA repair. The regulation of RelA by USP48 has been investigated in detail, but the domains of USP48 and RelA for direct interaction are not known. In this study we report that USP48 interacts physically with RelA in the nucleus. Further, we show by overexpression of truncated proteins that the catalytic USP domain of USP48 interacts with the N-terminal region of the Rel homology domain (RHD) of RelA. This study provides first evidence that the USP domain of USP48 is important for the physical association with substrate proteins, and a suitable target for small molecule inhibitors for therapeutic intervention strategies.


Assuntos
Domínio Catalítico , Homologia Estrutural de Proteína , Fator de Transcrição RelA/química , Fator de Transcrição RelA/metabolismo , Proteases Específicas de Ubiquitina/química , Proteases Específicas de Ubiquitina/metabolismo , Núcleo Celular/metabolismo , Células HeLa , Humanos , Ligação Proteica
2.
J Cell Mol Med ; 20(1): 58-70, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26463447

RESUMO

Cullin-RING-ubiquitin-ligase (CRL)-dependent ubiquitination of the nuclear factor kappa B (NF-κB) inhibitor IκBα and its subsequent degradation by the proteasome usually precede NF-κB/RelA nuclear activity. Through removal of the CRL-activating modification of their cullin subunit with the ubiquitin (Ub)-like modifier NEDD8, the COP9 signalosome (CSN) opposes CRL Ub-ligase activity. While RelA phosphorylation was observed to mediate NF-κB activation independent of Ub-proteasome-pathway (UPP)-dependent turnover of IκBα in some studies, a strict requirement of the p97/VCP ATPase for both, IκBα degradation and NF-κB activation, was reported in others. In this study, we thus aimed to reconcile the mechanism for tumour necrosis factor (TNF)-induced NF-κB activation. We found that inducible phosphorylation of RelA is accomplished in an IKK-complex-dependent manner within the NF-κB/RelA-IκBα-complex contemporaneous with the phosphorylation of IκBα, and that RelA phosphorylation is not sufficient to dissociate NF-κB/RelA from IκBα. Subsequent to CRL-dependent IκBα ubiquitination functional p97/VCP is essentially required for efficient liberation of (phosphorylated) RelA from IκBα, preceding p97/VCP-promoted timely and efficient degradation of IκBα as well as simultaneous NF-κB/RelA nuclear translocation. Collectively, our data add new facets to the knowledge about maintenance of IκBα and RelA expression, likely depending on p97/VCP-supported scheduled basal NF-κB activity, and the mechanism of TNF-induced NF-κB activation.


Assuntos
Adenosina Trifosfatases/fisiologia , Proteínas de Ciclo Celular/fisiologia , Inibidor de NF-kappaB alfa/metabolismo , Fator de Transcrição RelA/metabolismo , Ubiquitinação , Complexo do Signalossomo COP9 , Proteínas Culina/metabolismo , Células HeLa , Humanos , Complexos Multiproteicos/metabolismo , Proteína NEDD8 , Peptídeo Hidrolases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Proteólise , Fator de Necrose Tumoral alfa/fisiologia , Ubiquitinas/metabolismo , Proteína com Valosina
3.
Biochim Biophys Acta ; 1853(2): 453-69, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25486460

RESUMO

Diligent balance of nuclear factor kappa B (NF-κB) activity is essential owing to NF-κB's decisive role in cellular processes including inflammation, immunity and cell survival. Ubiquitin/proteasome-system (UPS)-dependent degradation of activated NF-κB/RelA involves the cullin-RING-ubiquitin-ligase (CRL) ECS(SOCS1). The COP9 signalosome (CSN) controls ubiquitin (Ub) ligation by CRLs through the removal of the CRL-activating Ub-like modifier NEDD8 from their cullin subunits and through deubiquitinase (DUB) activity of associated DUBs. However, knowledge about DUBs involved in the regulation of NF-κB activity within the nucleus is scarce. In this study we observed that USP48, a DUB of hitherto ill-defined function identified through a siRNA screen, associates with the CSN and RelA in the nucleus. We show that USP48 trims rather than completely disassembles long K48-linked free and substrate-anchored Ub-chains, a catalytic property only shared with ataxin-3 (Atx3) and otubain-1 (OTU1), and that USP48 Ub-chain-trimming activity is regulated by casein-kinase-2 (CK2)-mediated phosphorylation in response to cytokine-stimulation. Functionally, we demonstrate for the first time the CSN and USP48 to cooperatively stabilize the nuclear pool of RelA, thereby facilitating timely induction and shutoff of NF-κB target genes. In summary, this study demonstrates that USP48, a nuclear DUB regulated by CK2, controls the UPS-dependent turnover of activated NF-κB/RelA in the nucleus together with the CSN. Thereby USP48 contributes to a timely control of immune responses.


Assuntos
Núcleo Celular/metabolismo , Lisina/metabolismo , Complexos Multiproteicos/metabolismo , Peptídeo Hidrolases/metabolismo , Fator de Transcrição RelA/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Ubiquitina/metabolismo , Biocatálise/efeitos dos fármacos , Complexo do Signalossomo COP9 , Caseína Quinase II/metabolismo , Núcleo Celular/efeitos dos fármacos , Sequência Consenso , Células HEK293 , Células HeLa , Humanos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitinação/efeitos dos fármacos
4.
Int J Med Microbiol ; 303(8): 548-52, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23972614

RESUMO

Colonization of the gastric epithelium by Helicobacter pylori induces the transcription factor nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) and the innate immune response. Virulent strains of H. pylori carry a cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS). Recent publications have shown controversial data regarding the role of the T4SS and the effector protein cytotoxin associated gene A (CagA), which becomes translocated by the T4SS into the eukaryotic epithelial cell, in H. pylori-induced NF-κB activation. Thus, this study analyses by using three different H. pylori strains (P1, B128 and G27) whether CagA is required to initiate activation of different molecules of inhibitors of kappa B (IκB) and the NF-κB transcription factor RelA. We provide experimental evidence that H. pylori induces phosphorylation of NF-κB inhibitors IκBα, IκBß and IκBɛ, and degradation of IκBα. Further, H. pylori stimulates phosphorylation of RelA at amino acids S536, S468 and S276, promotes DNA binding of RelA, and interleukin 8 (IL-8) gene expression in a T4SS-, but CagA-independent manner at early time points.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Sistemas de Secreção Bacterianos/imunologia , Inativação Gênica , Helicobacter pylori/imunologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ativação Transcricional , Humanos , Fosforilação , Processamento de Proteína Pós-Traducional
5.
PLoS Pathog ; 9(6): e1003455, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23825949

RESUMO

The facultative intracellular bacterium Listeria monocytogenes (Lm) may cause severe infection in humans and livestock. Control of acute listeriosis is primarily dependent on innate immune responses, which are strongly regulated by NF-κB, and tissue protective factors including fibrin. However, molecular pathways connecting NF-κB and fibrin production are poorly described. Here, we investigated whether the deubiquitinating enzyme CYLD, which is an inhibitor of NF-κB-dependent immune responses, regulated these protective host responses in murine listeriosis. Upon high dose systemic infection, all C57BL/6 Cyld(-/-) mice survived, whereas 100% of wildtype mice succumbed due to severe liver pathology with impaired pathogen control and hemorrhage within 6 days. Upon in vitro infection with Lm, CYLD reduced NF-κB-dependent production of reactive oxygen species, interleukin (IL)-6 secretion, and control of bacteria in macrophages. Furthermore, Western blot analyses showed that CYLD impaired STAT3-dependent fibrin production in cultivated hepatocytes. Immunoprecipitation experiments revealed that CYLD interacted with STAT3 in the cytoplasm and strongly reduced K63-ubiquitination of STAT3 in IL-6 stimulated hepatocytes. In addition, CYLD diminished IL-6-induced STAT3 activity by reducing nuclear accumulation of phosphorylated STAT3. In vivo, CYLD also reduced hepatic STAT3 K63-ubiquitination and activation, NF-κB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis. In vivo neutralization of IL-6 by anti-IL-6 antibody, STAT3 by siRNA, and fibrin by warfarin treatment, respectively, demonstrated that IL-6-induced, STAT3-mediated fibrin production significantly contributed to protection in Cyld(-/-) mice. In addition, in vivo Cyld siRNA treatment increased STAT3 phosphorylation, fibrin production, pathogen control and survival of Lm-infected WT mice illustrating that therapeutic inhibition of CYLD augments the protective NF-κB/IL-6/STAT3 pathway and fibrin production.


Assuntos
Cisteína Endopeptidases/metabolismo , Fibrina/biossíntese , Interleucina-6/metabolismo , Listeria monocytogenes/metabolismo , Listeriose/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Anticoagulantes/farmacologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Enzima Desubiquitinante CYLD , Fibrina/genética , Fibrina/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Listeria monocytogenes/imunologia , Listeriose/tratamento farmacológico , Listeriose/genética , Listeriose/imunologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/biossíntese , NADPH Oxidases/genética , NADPH Oxidases/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética , Ubiquitinação/imunologia , Varfarina/farmacologia
6.
Proc Natl Acad Sci U S A ; 110(29): 11845-50, 2013 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-23818606

RESUMO

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-κB activation in mammals. It is an evolutionarily conserved eight-protein complex with subunits CSN1 to CSN8 named following the descending order of molecular weights. Here, we report the crystal structure of the largest CSN subunit, CSN1 from Arabidopsis thaliana (atCSN1), which belongs to the Proteasome, COP9 signalosome, Initiation factor 3 (PCI) domain containing CSN subunit family, at 2.7 Å resolution. In contrast to previous predictions and distinct from the PCI-containing 26S proteasome regulatory particle subunit Rpn6 structure, the atCSN1 structure reveals an overall globular fold, with four domains consisting of helical repeat-I, linker helix, helical repeat-II, and the C-terminal PCI domain. Our small-angle X-ray scattering envelope of the CSN1-CSN7 complex agrees with the EM structure of the CSN alone (apo-CSN) and suggests that the PCI end of each molecule may mediate the interaction. Fitting of the CSN1 structure into the CSN-Skp1-Cul1-Fbox (SCF) EM structure shows that the PCI domain of CSN1 situates at the hub of the CSN for interaction with several other subunits whereas the linker helix and helical repeat-II of CSN1 contacts SCF using a conserved surface patch. Furthermore, we show that, in human, the C-terminal tail of CSN1, a segment not included in our crystal structure, interacts with IκBα in the NF-κB pathway. Therefore, the CSN complex uses multiple mechanisms to hinder NF-κB activation, a principle likely to hold true for its regulation of many other targets and pathways.


Assuntos
Proteínas de Arabidopsis/química , Arabidopsis/química , Modelos Moleculares , NF-kappa B/antagonistas & inibidores , Conformação Proteica , Sequência de Aminoácidos , Complexo do Signalossomo COP9 , Clonagem Molecular , Cristalografia por Raios X , Humanos , Proteínas I-kappa B/metabolismo , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Dados de Sequência Molecular , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Alinhamento de Sequência , Homologia de Sequência , Especificidade da Espécie
7.
Biochem Soc Trans ; 38(Pt 1): 156-61, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20074051

RESUMO

The transcription factor NF-kappaB (nuclear factor kappaB) exerts crucial functions in the regulation of innate and adaptive immune responses, wound healing and tissue maintenance and in the development of immune cells. Tight control of NF-kappaB is essential for an efficient defence against pathogens and environmental stress to protect organisms from inflammatory diseases including cancer. An involvement of the CSN (COP9 signalosome) in the regulation of NF-kappaB has been discovered recently. The CSN is a conserved multiprotein complex, which mainly functions in the control of proteolysis. Here, we review recent observations indicating important roles of the CSN in the control of NF-kappaB in innate immunity, as well as T-cell activation and maturation.


Assuntos
Imunidade Inata/fisiologia , Complexos Multiproteicos/metabolismo , NF-kappa B/metabolismo , Peptídeo Hidrolases/metabolismo , Animais , Complexo do Signalossomo COP9 , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
8.
Cell Signal ; 22(3): 395-403, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19879355

RESUMO

It is supposed that human pathogens, e.g. Helicobacter pylori abuse lipid raft domains on the host cell plasma membrane to infect the cell. Investigating DRM-associated molecules we identified the transmembrane adapter proteins (TRAPs), non-T cell activation linker (NTAL) and lymphocyte-specific protein tyrosine kinase (Lck)-interacting membrane protein (LIME) to be regulated by H. pylori in the human epithelial cell line HCA-7. Up to now, raft-associated TRAPs were exclusively described to mediate signal propagation downstream of antigen receptors. Our results posed the question whether these proteins adopt a role in H. pylori-infected epithelial cells too. Our studies revealed that H. pylori induces tyrosine phosphorylation of NTAL as well as LIME within 15 min of infection. We observed that activated NTAL and LIME bind to the Src homology 2 (SH2)-domain of growth factor receptor-bound protein 2 (Grb2) within 15 to 30 min of infection and associate with the c-Met receptor. Further, NTAL has a contributory role in regulating H. pylori-induced extracellular signal-regulated kinase (ERK) activation. After suppression of NTAL protein levels by siRNA, ERK phosphorylation was reduced to approximately 50%. Additionally, the knockdown of NTAL suppressed the phosphorylation of cytosolic phospholipase A2 (cPLA2). Activated cPLA2 catalyzes the release of arachidonic acid (AA), whose metabolites are pivotal mediators in the H. pylori-induced inflammatory response. Thus, we propose that NTAL participates in the activation of the c-Met-Grb2-ERK-cPLA2 signalling cascade at early stages of H. pylori infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Helicobacter pylori/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Linhagem Celular Tumoral , Proteína Adaptadora GRB2/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Fosfolipases A2/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Interferente Pequeno/metabolismo
10.
EMBO Rep ; 10(6): 642-8, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19444310

RESUMO

The Carma1-Bcl10-Malt1 (CBM) complex connects T-cell receptor (TCR) signalling to the canonical IkappaB kinase (IKK)/NF (nuclear factor)-kappaB pathway. Earlier studies have indicated that the COP9 signalosome (CSN), a pleiotropic regulator of the ubiquitin/26S proteasome system, controls antigen responses in T cells. The CSN is required for the degradation of the NF-kappaB inhibitor IkappaBalpha, but other molecular targets involved in T-cell signalling remained elusive. Here, we identify the CSN subunit 5 (CSN5) as a new interactor of Malt1 and Carma1. T-cell activation triggers the recruitment of the CSN to the CBM complex, and CSN downregulation impairs TCR-induced IKK activation. Furthermore, the CSN is required for maintaining the stability of Bcl10 in response to T-cell activation. Taken together, our data provide evidence for a functional link between the evolutionarily conserved CSN and the adaptive immunoregulatory CBM complex in T cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspases/metabolismo , Guanilato Ciclase/metabolismo , Ativação Linfocitária/imunologia , Complexos Multiproteicos/metabolismo , Proteínas de Neoplasias/metabolismo , Peptídeo Hidrolases/metabolismo , Linfócitos T/imunologia , Proteína 10 de Linfoma CCL de Células B , Complexo do Signalossomo COP9 , Ativação Enzimática , Humanos , Quinase I-kappa B/metabolismo , Células Jurkat , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Ligação Proteica , Estabilidade Proteica , Subunidades Proteicas , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Linfócitos T/enzimologia , Ubiquitinação
11.
Adv Appl Bioinform Chem ; 2: 125-38, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-21918620

RESUMO

Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB). Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD), receptor-interacting protein 1 (RIP1), and protein inhibitor of activated STAT y (PIASy) as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio-and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.

12.
EMBO J ; 26(6): 1532-41, 2007 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-17318178

RESUMO

The COP9 signalosome (CSN) is a conserved protein complex that regulates assembly and activity of cullin-RING ubiquitin ligases (CRLs). Ubiquitin-dependent degradation of the NF-kappaB inhibitor IkappaBalpha preceeds nuclear translocation of NF-kappaB. For the first time, we show here an inducible interaction of the CSN with IkappaBalpha and that the CSN controls IkappaBalpha and NF-kappaB activity. Strikingly, disruption of the CSN by a small interfering RNA-mediated knockdown of single CSN subunits results in a reduced re-accumulation of IkappaBalpha and prolonged nuclear translocation of NF-kappaB in TNFalpha-stimulated cells. The control of IkappaBalpha by the CSN is regulated by deubiquitinylation of IkappaBalpha conferred by the CSN-associated deubiquitinylase USP15. Protein expression levels of cullin1 and the CRL substrate adapter beta-TrCP are reduced in nonstimulated cells with a disrupted function of the CSN, which might account for an impaired basal turnover of IkappaBalpha. We propose that the CSN controls both CRL activity and stability of the CRL substrate IkappaBalpha. In consequence, basal and signal-induced CRL-dependent turnover of IkappaBalpha is precisely adapted to specific cellular needs.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Proteínas I-kappa B/metabolismo , Complexos Multiproteicos/metabolismo , NF-kappa B/metabolismo , Peptídeo Hidrolases/metabolismo , Ubiquitinas/metabolismo , Complexo do Signalossomo COP9 , Ensaio de Desvio de Mobilidade Eletroforética , Endopeptidases/metabolismo , Células HeLa , Humanos , Imunoprecipitação , Modelos Biológicos , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , Proteases Específicas de Ubiquitina
13.
Biol Chem ; 387(1): 79-86, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16497167

RESUMO

Helicobacter pylori, the etiological agent of various human gastric diseases, induces the transcription factor nuclear factor kappaB (NF-kappaB) and proinflammatory cytokines/chemokines. We have characterised the direct interaction between p21-activated kinase 1 (PAK1) and NF-kappaB-inducing kinase (NIK) in H. pylori-infected epithelial cells. The dimerisation (DI) motif, which is part of the NH2-terminal autoregulatory domain of PAK1, is critical for this interaction, whereas NIK forms complexes with PAK1 through its carboxy-terminal IkappaB kinase alpha (IKKalpha) binding site. Since the identified interaction sites are also crucial for the binding of activator (Rac/Cdc42 in the case of PAK1) or effector molecules (IKKalpha in the case of NIK), sequential stepwise signalling is suggested. Furthermore, we show that mitogen-activated protein kinase kinase kinases (MAP3K), like TPL2 (tumour progression locus 2) and transforming growth factor beta-activated kinase 1 (TAK1), have no impact on H. pylori-induced activation of NF-kappaB. These results identify the roles of PAK1 and NIK in a unique pathway involved in H. pylori-induced NF-kappaB activation, which is crucial for the induction of the innate immune response.


Assuntos
Células Epiteliais/imunologia , Helicobacter pylori/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sítios de Ligação , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Mucosa Gástrica/citologia , Homeostase , Humanos , Quinase I-kappa B/metabolismo , Imunidade Inata , Proteínas Serina-Treonina Quinases/química , Estrutura Terciária de Proteína/fisiologia , Quinases Ativadas por p21 , Quinase Induzida por NF-kappaB
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