RESUMO
Mutation and prevalence of pathogenic viruses prompt the development of broad-spectrum antiviral strategies. Viperin is a potent antiviral protein that inhibits a broad range of viruses. Unexpectedly, we found that Viperin protein production in epithelium is defective in response to both viruses and interferons (IFNs). We further revealed that viruses and IFNs stimulate expression of the acetyltransferase HAT1, which induces Lys197-acetylation on Viperin. Viperin acetylation in turn recruits UBE4A that stimulates K6-linked polyubiquitination at Lys206 of Viperin, leading to Viperin protein degradation. Importantly, UBE4A deficiency restores Viperin protein production in epithelium. We then designed interfering peptides (IPs) to inhibit UBE4A binding with Viperin. We found that VIP-IP3 rescues Viperin protein production in epithelium and therefore enhances cellular antiviral activity. VIP-IP3 renders mice more resistant to viral infection. These findings could provide strategies for both enhancing host broad-spectrum antiviral response and improving the efficacy of IFN-based antiviral therapy.
Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/virologia , Proteínas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Animais , Linhagem Celular , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Humanos , Interferons/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Peptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
Disorders of the ubiquitin-proteasome system (UPS) are known to influence the incidence and mortality of various diseases. It remains largely unknown whether and how the UPS affects the onset and progression of acute graft-verus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study demonstrated that the deubiquitinase OTUD1 is an essential regulator of aGVHD. Activation of CD4+ T cells after allo-HSCT, elevated the protein levels of OTUD1, which in turn interacted with the Notch2-ICD (NICD) to cleave the ubiquitin of NICD at the K1770 site, thereby inducing NICD protein accumulations in T cells. OTUD1-driven NICD signaling promoted the differentiation and functions of Th1 and Th17 cells and amplified the cascade of aGVHD. Moreover, by screening a FDA-approved drugs library the study identified dapagliflozin as an inhibitor targeting the OTUD1/NICD axis. Dapagliflozin administration significantly prolonged the survival of aGVHD mice. This study characterized a previously unknown role of OTUD1 in T cell-mediated allogeneic responses and provided a promising therapeutic strategy to target OTUD1 for the alleviation of aGVHD.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Camundongos , Doença Aguda , Linfócitos T CD4-Positivos/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , UbiquitinasRESUMO
ACE2 is a major receptor for cellular entry of SARS-CoV-2. Despite advances in targeting ACE2 to inhibit SARS-CoV-2 binding, strategies to flexibly and sufficiently reduce ACE2 levels for the prevention of SARS-CoV-2 infection have not been explored. Here, we reveal vitamin C (VitC) administration as a potent strategy to prevent SARS-CoV-2 infection. VitC reduces ACE2 protein levels in a dose-dependent manner, while even a partial reduction in ACE2 levels can greatly inhibit SARS-CoV-2 infection. Further studies reveal that USP50 is a crucial regulator of ACE2 levels. VitC blocks the USP50-ACE2 interaction, thus promoting K48-linked polyubiquitination of ACE2 at Lys788 and subsequent degradation of ACE2 without affecting its transcriptional expression. Importantly, VitC administration reduces host ACE2 levels and greatly blocks SARS-CoV-2 infection in mice. This study reveals that ACE2 protein levels are down-regulated by an essential nutrient, VitC, thereby enhancing protection against infection of SARS-CoV-2 and its variants.
Assuntos
COVID-19 , Animais , Camundongos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Ácido Ascórbico/farmacologiaRESUMO
IMPORTANCE: EV71 poses a significant health threat to children aged 5 and below. The process of EV71 infection and replication is predominantly influenced by ubiquitination modifications. Our previous findings indicate that EV71 prompts the activation of host deubiquitinating enzymes, thereby impeding the host interferon signaling pathway as a means of evading the immune response. Nevertheless, the precise mechanisms by which the host employs ubiquitination modifications to hinder EV71 infection remain unclear. The present study demonstrated that the nonstructural protein 2Apro, which is encoded by EV71, exhibits ubiquitination and degradation mediated by the host E3 ubiquitin ligase SPOP. In addition, it is the first report, to our knowledge, that SPOP is involved in the host antiviral response.
Assuntos
Cisteína Endopeptidases , Enterovirus Humano A , Infecções por Enterovirus , Interações entre Hospedeiro e Microrganismos , Ubiquitina-Proteína Ligases , Ubiquitina , Ubiquitinação , Proteínas Virais , Criança , Humanos , Enterovirus Humano A/enzimologia , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Cisteína Endopeptidases/metabolismoRESUMO
High-salt diets have recently been implicated in hypertension, cardiovascular disease, and autoimmune disease. However, whether and how dietary salt affects host antiviral response remain elusive. Here, we report that high salt induces an instant reduction in host antiviral immunity, although this effect is compromised during a long-term high-salt diet. Further studies reveal that high salt stimulates the acetylation at Lys663 of p97, which promotes the recruitment of ubiquitinated proteins for proteasome-dependent degradation. p97-mediated degradation of the deubiquitinase USP33 results in a deficiency of Viperin protein expression during viral infection, which substantially attenuates host antiviral ability. Importantly, switching to a low-salt diet during viral infection significantly enhances Viperin expression and improves host antiviral ability. These findings uncover dietary salt-induced regulation of ubiquitinated cellular proteins and host antiviral immunity, and could offer insight into the daily consumption of salt-containing diets during virus epidemics.
Assuntos
Fatores de Restrição Antivirais/imunologia , Imunidade Inata/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Viroses , Humanos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Ubiquitina Tiolesterase , Ubiquitinação , Viroses/imunologia , Vírus/patogenicidadeRESUMO
Type I interferon (IFN-I) is a common biological molecule used for the treatment of viral diseases. However, the clinical antiviral efficacy of IFN-I needs to be greatly improved. In this study, IFN-I receptor 2 (IFNAR2) was revealed to undergo degradation at the protein level in cells treated with IFN-I for long periods of time. Further studies found a physical interaction between the E3 ubiquitin ligase midline-1 (MID1) and IFNAR2. As a consequence, MID1 induced both K48- and K63-linked polyubiquitination of IFNAR2, which promoted IFNAR2 protein degradation in a lysosome-dependent manner. Conversely, knockdown of MID1 largely restricted IFN-I-induced degradation of IFNAR2. Importantly, MID1 regulated the strength of IFN-I signalling and IFN-I-induced antiviral activity. These findings reveal a regulatory mechanism of IFNAR2 ubiquitination and protein stability in IFN-I signalling, which could provide a potential target for improving the antiviral efficacy of IFN-I.
Assuntos
Interferon Tipo I , Ubiquitina-Proteína Ligases , Antivirais/farmacologia , Interferon Tipo I/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Viral infection is a serious threat to both normal population and clinical patients. STAT1 plays central roles in host defense against viral infection. How STAT1 protein maintains stable in different conditions remains largely unknown. Here, we identified BRCC36 as a potent regulator of STAT1 protein stability. Mechanistically, BRCC36 maintains STAT1 levels by utilizing USP13 to form a balanced complex for antagonizing Smurf1-mediated degradation. Importantly, cellular BRCC36 deficiency results in rapid downregulation of STAT1 during viral infection, whereas a supplement of BRCC36 maintains STAT1 protein levels and host antiviral immunity in vivo. Moreover, we revealed that BRCC36 expression was downregulated in allogeneic HSC transplantation (allo-HSCT) mice that showed increased susceptibility to viral infection. Supplementing BRCC36 enhanced antiviral response of allo-HSCT mice by maintaining STAT1 stability. This study uncovers a critical role of BRCC36 in STAT1 protein stability and could provide potential strategies for enhancing clinical antiviral therapy.
Assuntos
Antivirais/metabolismo , Enzimas Desubiquitinantes/metabolismo , Fator de Transcrição STAT1/metabolismo , Viroses/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HCT116 , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
CREB-binding protein (CBP) participates in numerous transcription events. However, cell-intrinsic inhibitors of CBP are poorly defined. Here, we found that cellular USP12 interacts with the HAT domain of CBP and inhibits CBP's acetyltransferase activity. Interestingly, USP12 positively regulates interferon (IFN) antiviral signaling independently of its deubiquitinase activity. Furthermore, we found that in IFN signaling USP12 translocates from the cytoplasm to the nucleus. The decrease in cytoplasmic USP12 facilitates CBP-induced acetylation and activation of IFN signaling proteins in the cytoplasm. Moreover, USP12 accumulation in the nucleus blocks CBP-induced acetylation of phosphorylated STAT1 (p-STAT1) and therefore inhibits the dephosphorylation effects of TCPTP on p-STAT1, which finally maintains nuclear p-STAT1 levels and IFN antiviral efficacy. USP12 nuclear translocation extends our understanding of the regulation of the strength of IFN antiviral signaling. Our study uncovers a cell-intrinsic regulation of CBP acetyltransferase activity and may provide potential strategies for IFN-based antiviral therapy.
Assuntos
Proteína de Ligação a CREB/antagonistas & inibidores , Interferons/fisiologia , Ubiquitina Tiolesterase/metabolismo , Acetilação , Animais , Antivirais/metabolismo , Proteína de Ligação a CREB/metabolismo , Citoplasma/metabolismo , Inibidores Enzimáticos/metabolismo , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Domínios Proteicos , Células RAW 264.7 , Fator de Transcrição STAT1/metabolismo , Transdução de SinaisRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease with nearly 1.6 billion patients worldwide and an incidence of 0.5-1%. In recent years, basic and clinical studies have revealed that immune cell responses and corresponding secretion of inflammatory factors are important in the control of RA development. Our study found that a natural plant ingredient, menthone, could be used as a potential antirheumatism compound. In vivo observations demonstrated that menthone alleviates collagen II-induced arthritis (CIA) in mice. Furthermore, we found that menthone regulates the number of Th1 and Th17 cells in CIA mice. Importantly, menthone significantly inhibits the release of pro-inflammatory cytokines, including TNF-α, IL-1ß, and IL-6, in CIA mice. Our study suggests a potential component for the development of drugs to treat rheumatoid arthritis.
Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citocinas , Humanos , Mentol , Camundongos , Camundongos Endogâmicos DBA , Células Th17RESUMO
Interferon regulatory factor 3 (IRF3) is a critical transcription factor for inducing production of type I interferons (IFN-I) and regulating host antiviral response. Although IRF3 activation during viral infection has been extensively studied, the inhibitory regulation of IRF3 remains largely unexplored. Here, we revealed that Midline-1 (MID1) is a ubiquitin E3 ligase of IRF3 that plays essential roles in regulating the production of IFN-I. We found that MID1 physically interacts with IRF3 and downregulates IRF3 protein levels. Next, we demonstrated that MID1 can induce K48-linked polyubiquitination of IRF3, thus lowing the protein stability of IRF3. Our further studies identified Lys313 as a major ubiquitin acceptor lysine of IRF3 induced by MID1. Finally, MID1-mediated ubiquitination and degradation of IRF3 restrict IFN-I production and cellular antiviral response. This study uncovers a role of MID1 in regulating innate antiviral immunity and may provide a potential target for enhancing host antiviral activity.
Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Sistemas CRISPR-Cas , Células HEK293 , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteólise , RNA Interferente Pequeno/genética , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
During RNA virus infection, the adaptor protein MAVS recruits TRAF3 and TRAF6 to form a signalosome, which is critical to induce the production of type I interferons (IFNs) and proinflammatory cytokines. While activation of the MAVS/TRAF3/TRAF6 signalosome is well studied, the negative regulation of the signalosome remains largely unknown. Here we report that RNA viruses specifically promote the deubiquitinase OTUD1 expression by NF-κB-dependent mechanisms at the early stage of viral infection. Furthermore, OTUD1 upregulates protein levels of intracellular Smurf1 by removing Smurf1 ubiquitination. Importantly, RNA virus infection promotes the binding of Smurf1 to MAVS, TRAF3 and TRAF6, which leads to ubiquitination-dependent degradation of every component of the MAVS/TRAF3/TRAF6 signalosome and subsequent potent inhibition of IFNs production. Consistently, OTUD1-deficient mice produce more antiviral cytokines and are more resistant to RNA virus infection. Our findings reveal a novel immune evasion mechanism exploited by RNA viruses, and elucidate a negative feedback loop of MAVS/TRAF3/TRAF6 signaling mediated by the OTUD1-Smurf1 axis during RNA virus infection.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade Inata/imunologia , Vírus de RNA/fisiologia , Fator 3 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Interferon beta/genética , Interferon beta/metabolismo , Camundongos , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/prevenção & controle , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/imunologiaRESUMO
Ataxin-3 (ATXN3) belongs to the Josephin family of deubiquitinases. So far, ATXN3 is majorly linked to the neurodegenerative disease, Machado-Joseph disease. The role of ATXN3 in the antiviral function has not been explored, and the in vivo deubiquitinating activity of ATXN3 remains largely unknown. In this study, we report that ATXN3 is an important positive regulator of type I IFN (IFN-I)-mediated antiviral activity in murine primary lung cells and human epithelial and fibroblast cell lines. We clarify that ATXN3 does not promote IFN-I production, but enhances the IFN-I-mediated signaling pathway. Furthermore, ATXN3 physically interacts with histone deacetylase 3 (HDAC3) and upregulates the level of HDAC3 protein. Moreover, ATXN3 deubiquitinates HDAC3, thereby enhancing HDAC3 protein stability. Interestingly, the interaction between ATXN3 and HDAC3 increases during viral infection, which promotes IFN-I-induced signaling in murine primary lung cells. Finally, we reveal the ATXN3/HDAC3 axis-mediated regulation of IFN-I antiviral response. These findings reveal a novel biological function of ATXN3 and an important antiviral mechanism by which the deubiquitinase ATXN3 positively regulates IFN-I antiviral response, and they may provide a novel strategy for enhancing IFN-based antiviral therapy.
Assuntos
Ataxina-3/metabolismo , Histona Desacetilases/metabolismo , Doença de Machado-Joseph/genética , Mucosa Respiratória/imunologia , Viroses/imunologia , Animais , Ataxina-3/genética , Linhagem Celular , Humanos , Imunidade , Imunomodulação , Interferon Tipo I/metabolismo , Camundongos , Ligação Proteica , Estabilidade Proteica , UbiquitinaçãoRESUMO
Type-I interferons (IFN-I) are widely used for antiviral immunotherapy in clinic. Therefore, identification of the regulators of IFN-I antiviral activity is important for developing novel targets for IFN-based antiviral therapy. Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1) is critical for cellular inflammatory responses. However, the roles of MCPIP1 in interferons (IFNs)-mediated antiviral immunity are unexplored. In this study, we demonstrate for the first time that MCPIP1 is an important positive regulator of IFNs antiviral activity. We found that MCPIP1 can promote innate antiviral immunity independently of both its RNase and deubiquitinase activity. Furthermore, we reveal that MCPIP1 is an IFN-induced positive feedback signal molecule which promotes IFN-I-mediated antiviral efficacy. Mechanistically, MCPIP1 does not affect the activation of JAK/STAT upstream of IFN-I signaling, but significantly promotes IFN-I signaling by enhancing ISRE promoter activity and expression of interferon-stimulated genes (ISGs). And MCPIP1-mediated activation of IFN-I signaling is independently of its RNase and deubiquitinase activity. These findings uncover a novel innate antiviral mechanism mediated by the IFN-MCPIP1 axis, and may provide potential targets for enhancing IFNs antiviral therapy.
Assuntos
Imunidade Inata , Interferon Tipo I/imunologia , Ribonucleases/imunologia , Fatores de Transcrição/imunologia , Viroses/imunologia , Linhagem Celular , Humanos , Interferon Tipo I/genética , Regiões Promotoras Genéticas , Elementos de Resposta/genética , Transdução de Sinais/imunologia , Ativação Transcricional , Transfecção , Estomatite Vesicular/imunologia , Vesiculovirus/imunologiaRESUMO
STAT1 is a critical transcription factor for regulating host antiviral defenses. STAT1 activation is largely dependent on phosphorylation at tyrosine 701 site of STAT1 (pY701-STAT1). Understanding how pY701-STAT1 is regulated by intracellular signaling remains a major challenge. Here we find that pY701-STAT1 is the major form of ubiquitinated-STAT1 induced by interferons (IFNs). While total STAT1 remains relatively stable during the early stages of IFNs signaling, pY701-STAT1 can be rapidly downregulated by the ubiquitin-proteasome system. Moreover, ubiquitinated pY701-STAT1 is located predominantly in the nucleus, and inhibiting nuclear import of pY701-STAT1 significantly blocks ubiquitination and downregulation of pY701-STAT1. Furthermore, we reveal that the deubiquitinase USP2a translocates into the nucleus and binds to pY701-STAT1, and inhibits K48-linked ubiquitination and degradation of pY701-STAT1. Importantly, USP2a sustains IFNs-induced pY701-STAT1 levels, and enhances all three classes of IFNs- mediated signaling and antiviral activity. To our knowledge, this is the first identified deubiquitinase that targets activated pY701-STAT1. These findings uncover a positive mechanism by which IFNs execute efficient antiviral signaling and function, and may provide potential targets for improving IFNs-based antiviral therapy.
Assuntos
Núcleo Celular/metabolismo , Endopeptidases/imunologia , Interferons/imunologia , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/imunologia , Viroses/imunologia , Linhagem Celular , Endopeptidases/metabolismo , Citometria de Fluxo , Humanos , Immunoblotting , Imunoprecipitação , Microscopia de Fluorescência , Transporte Proteico/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT1/metabolismo , Vírus Sendai/imunologia , Transfecção , Ubiquitina Tiolesterase , Ubiquitinação , Vesiculovirus/imunologiaRESUMO
Ubiquitin-mediated proteolysis regulates cellular levels of various proteins, and therefore plays important roles in controlling cell signaling and disease progression. The Skp1-Cul1-F-box ubiquitin ligase ß-TrCP is recognized as an important negative regulator for numerous key signaling proteins. Recently, the deubiquitinases (DUBs) have turned out to be essential to regulate signaling pathways related to human diseases. However, whether ß-TrCP is able to regulate the deubiquitinase family members remains largely unexplored. Here, we found that ß-TrCP downregulated cellular levels of endogenous USP33. We also revealed that ß-TrCP interacted with USP33 independently of the classic binding motif for ß-TrCP, and mediated USP33 degradation via the ubiquitin proteasome pathway. Furthermore, we found that the WD40 motif of ß-TrCP and 201-400 amino acid motif of USP33 are required for the interaction between ß-TrCP and USP33. Consequently, ß-TrCP attenuated USP33-mediated inhibition of cell proliferation and cell invasion. Taken together, our study clarified that the E3 ligase ß-TrCP regulates cellular USP33 levels by the ubiquitin-proteasomal proteolysis.
Assuntos
Regulação da Expressão Gênica/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação/fisiologia , Repetições WD40/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Proteólise , Transdução de Sinais/genética , Ubiquitina/metabolismo , Ubiquitina Tiolesterase/genética , Proteínas Contendo Repetições de beta-Transducina/genéticaRESUMO
Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity. Here we unexpectedly found that IFN signaling promoted Lys48-linked ubiquitination and degradation of ADAR1-P110. Furthermore, we identified the E3 ligase ß transducin repeat-containing protein responsible for IFN-mediated ADAR1-P110 down-regulation. IFN signaling promoted the interaction between ß transducin repeat-containing protein and ADAR1-P110 as well as protein turnover of ADAR1-P110. Moreover, we found that both lysine 574 and 576 are essential for ADAR1-P110 ubiquitination. Critically, we demonstrated that down-regulation of ADAR1-P110 is required for IFN signaling to execute efficient antiviral activity during viral infections. These findings renew the understanding of the mechanisms by which IFN signaling acts to achieve antiviral functions and may provide potential targets for IFN-based antiviral therapy.
Assuntos
Adenosina Desaminase/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Ubiquitinação/fisiologia , Adenosina Desaminase/genética , Linhagem Celular , Humanos , Interferon Tipo I/genética , Proteínas de Ligação a RNA/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Ubiquitin-specific peptidase 5 (USP5) has been demonstrated to be critical for the production of Tumor Necrosis Factor-alpha (TNF-α), a pivotal mediator for inflammatory responses. Besides, USP5 regulates p53 activation and DNA repair. However, the mechanism underlying the regulation of USP5, especially its responsible E3 ligase is still unclear. Here we found that Smad ubiquitination regulatory factor 1 (Smurf1) down regulated protein expression of USP5, and the E3 enzyme activity of Smurf1 was required for this function. We also revealed that Smurf1 interacted with USP5 and mediated its degradation via the ubiquitin proteasome pathway. Consequently, Smurf1 inhibited the production of TNF-α through down-regulation of USP5. Taken together, our study for the first time clarified that the E3 ligase Smurf1 regulates USP5 protein stability and USP5-mediated TNF-α production through the ubiquitin proteasome pathway.
Assuntos
Endopeptidases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Ubiquitinação/fisiologia , Regulação para Baixo/fisiologia , Estabilidade Enzimática , Células HEK293 , Células HeLa , HumanosRESUMO
BACKGROUND: Socioeconomic status (SES) plays a crucial role in blood pressure (BP) control. SES may influence BP control through obesity indices, such as body mass index (BMI) and waist circumference (WC). This study aimed to understand the relationships between SES and BP control in the elderly hypertensive population, and to determine whether BMI and WC mediate the relationship between SES and BP control. METHODS: The study was conducted in Jia County, Henan Province, China, from 1 July to 31 August 2023. The 18,963 hypertensive people over 65 years old who were included in the National Basic Public Health Service Program were investigated. The study utilized questionnaire surveys to collect data on participants' demographic characteristics, disease history, lifestyle behaviors, antihypertensive medication, and measured height, weight, and blood pressure. SES was indexed by participants' self-reported educational level, family income, and occupation, and categorized into low, medium, and high groups by using latent category analysis (LCA). Logistic regression models were used to analyze the associations between SES and BP control. Obesity indicators, represented by BMI and WC, were included in mediation models to examine the indirect effects of BMI/WC on the association between SES and BP control. RESULTS: The mean age of 17,234 participants was 73.4 years and 9888 (57.4%) of the participants were female. The LCA results indicated the number of participants in low SES, middle SES, and high SES groups were 7760, 8347, and 1127, respectively. Compared with the low SES group, the odds ratios (ORs) and 95% confidence intervals (CIs) for the association of BP control with middle SES and high SES were 1.101 (1.031, 1.175), and 1.492 (1.312, 1.696). This association was similarly found in the subsequent subgroup analyses (p < 0.05). Compared with low SES, our findings further suggested that BMI (indirect effects: 95% CIs: -0.004--0.001; p < 0.001) and WC (indirect effects: 95% CIs: -0.003--0.001; p = 0.020) play a suppressing role in the association between high SES and BP control. CONCLUSIONS: Our study indicated that the elderly hypertensive population with high SES may have a better result for BP control. However, we found that BMI/WC plays a suppressing role in this association. This indicated that despite the better BP control observed in elderly hypertensive populations with high SES, BMI and WC might undermine this beneficial relationship. Therefore, implementing strategies for obesity prevention is an efficient way to maintain this beneficial association between high SES and BP control.
Assuntos
Pressão Sanguínea , Índice de Massa Corporal , Hipertensão , Obesidade , Classe Social , Circunferência da Cintura , Humanos , Feminino , Hipertensão/epidemiologia , Masculino , Idoso , Obesidade/epidemiologia , China/epidemiologia , Idoso de 80 Anos ou mais , Fatores de Risco , Anti-Hipertensivos/uso terapêuticoRESUMO
Healthy behavioral patterns could modulate organ functions to enhance the body's immunity. However, how exercise regulates antiviral innate immunity remains elusive. Here, we found that exercise promotes type I interferon (IFN-I) production in the liver and enhances IFN-I immune activity of the body. Despite the possibility that many exercise-induced factors could affect IFN-I production, we identified Gpld1 as a crucial molecule, and the liver as the major organ to promote IFN-I production after exercise. Exercise largely loses the efficiency to induce IFN-I in Gpld1-/- mice. Further studies demonstrated that exercise-produced 3-hydroxybutanoic acid (3-HB) critically induces Gpld1 expression in the liver. Gpld1 blocks the PP2A-IRF3 interaction, thus enhancing IRF3 activation and IFN-I production, and eventually improving the body's antiviral ability. This study reveals that exercise improves antiviral innate immunity by linking the liver metabolism to systemic IFN-I activity and uncovers an unknown function of liver cells in innate immunity.
Assuntos
Imunidade Inata , Fator Regulador 3 de Interferon , Interferon Tipo I , Fígado , Condicionamento Físico Animal , Animais , Masculino , Camundongos , Antivirais , Citocinas , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Fígado/metabolismo , Fígado/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Ubiquitinas , Glicosilfosfatidilinositol Diacilglicerol-Liase/metabolismoRESUMO
DEAD-box helicase (DDX) family members play differential roles in regulating innate antiviral immune response. However, the physiological roles played by DDX4 in antiviral innate immunity remain unclear. In this study, we unveiled that DDX4 acts as a positive regulatory molecule of Type-I interferon (IFN-I)-mediated antiviral activity. Our findings demonstrate that IFN-I upregulates DDX4 protein levels, and subsequently, overexpression of DDX4 enhances the IFN-I-mediated signaling pathway. This creates a positive feedback loop that amplifies the antiviral response. DDX4 was found to bind with deubiquitinase ubiquitin-specific protease 7 (USP7), leading to the disruption of the interaction between USP7 and suppressor of cytokine signaling 1 (SOCS1) and the subsequent degradation of SOCS1. This process enhances the antiviral function of IFN-I. Our findings provide new insights into the regulatory role of DDX4 in the IFN-I response.IMPORTANCEDDX4, identified as a putative RNA helicase that modulates RNA secondary structure through RNA binding, is primarily acknowledged for its role in regulating mRNA translation within the germline. Nevertheless, the extent of DDX4's involvement in the antiviral innate immune response remains largely unexplored. This study presents evidence of a previously unrecognized positive feedback loop between DDX4 and the antiviral response, suggesting that disruption of this loop may serve as a novel mechanism for viral evasion. Furthermore, our findings elucidate a positive regulatory mechanism by which the DDX4/USP7/SOCS1 axis mediates the antiviral activity of Type-I interferon, which provides new insight into strategies for improving the efficacy of IFN-based antiviral therapy.