RESUMO
Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation.
Assuntos
Imunidade Inata , Mitocôndrias , Transdução de Sinais , Proteínas com Motivo Tripartido , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/imunologia , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/imunologia , Animais , Viroses/imunologia , MitofagiaRESUMO
TRIM7 has been demonstrated to have significant roles in promoting host defense against viral infections and regulating immune signaling pathways. As an E3 ubiquitin ligase, it catalyzes the ubiquitination of various substrates, including adaptor proteins (MAVS and STING) and transcription factors (NF-κB and IRF3), thereby exerting positive or negative regulation on immune signal pathways. However, viruses have developed immune evasion mechanisms to counteract TRIM7. Some viruses can inhibit TRIM7 function by targeting it for degradation or sequestering it away from its targets. Moreover, TRIM7 may even facilitate viral infection by ubiquitinating viral proteins, including envelope proteins that are critical for tissue and species tropism. A comprehensive understanding of the interaction between TRIM7 and antiviral immunity is crucial for the development of innovative treatments for viral diseases.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Viroses , Evasão da Resposta Imune , NF-kappa B , Ubiquitina-Proteína Ligases/imunologia , Viroses/imunologia , Proteínas com Motivo Tripartido/imunologiaRESUMO
BACKGROUND: Neuroinflammation subsequent to traumatic brain injury (TBI) is important for the recovery of patients and is associated with neurodegenerative changes post-TBI. The tripartite motif containing 44 (TRIM44) protein is an E3 ligase involved in the regulation of immune function with no previously known link to TBI. This study explores the connection between TRIM44 and TBI. METHODS: After induction of TBI in rats by control cortex injury, TRIM44 expressions were determined with quantitative real-time reverse transcription polymerase chain reaction and Western blot, and Toll-like receptor 4 (TLR4)-NF-κB signaling was examined by the expression of TLR4, p65 phosphorylation, and the specific NF-κB transcription activity. The effects of TRIM44 knockdown on inflammation, neurological function, and TLR4-NF-κB signaling in TBI rats were revealed by the detection of proinflammatory cytokines and TLR4-NF-κB signaling molecules, modified neurological severity score, brain water content, and Evans blue permeability. RESULTS: We found that TRIM44 expression was significantly increased following TBI induction along with TLR4-NF-κB activation. Silencing of TRIM44 suppressed proinflammatory cytokine production, improved neurological outcomes, alleviated brain edema, and inhibited TLR4-NF-κB signaling in TBI rats. CONCLUSION: Our findings suggest that suppressing TRIM44 or modulation of relevant pathways may be a therapeutic strategy for TBI.
Assuntos
Lesões Encefálicas Traumáticas , Inflamação , Proteínas com Motivo Tripartido , Animais , Ratos , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/imunologia , Inflamação/genética , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/imunologiaRESUMO
The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade Inata , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Estomatite Vesicular/metabolismo , Vesiculovirus/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Chlorocebus aethiops , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Células HEK293 , Células HaCaT , Interações Hospedeiro-Patógeno , Humanos , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Transdução de Sinais , Células THP-1 , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação , Células Vero , Estomatite Vesicular/genética , Estomatite Vesicular/imunologia , Estomatite Vesicular/virologia , Vesiculovirus/patogenicidadeRESUMO
Infectious bursal disease virus (IBDV), a double-stranded RNA virus, causes immunosuppression and high mortality in 3-6-week-old chickens. Innate immune defense is a physical barrier to restrict viral replication. After viral infection, the host shows crucial defense responses, such as stimulation of antiviral effectors to restrict viral replication. Here, we conducted RNA-seq in avian cells infected by IBDV and identified TRIM25 as a host restriction factor. Specifically, TRIM25 deficiency dramatically increased viral yields, whereas overexpression of TRIM25 significantly inhibited IBDV replication. Immunoprecipitation assays indicated that TRIM25 only interacted with VP3 among all viral proteins, mediating its K27-linked polyubiquitination and subsequent proteasomal degradation. Moreover, the Lys854 residue of VP3 was identified as the key target site for the ubiquitination catalyzed by TRIM25. The ubiquitination site destroyed enhanced the replication ability of IBDV in vitro and in vivo. These findings demonstrated that TRIM25 inhibited IBDV replication by specifically ubiquitinating and degrading the structural protein VP3.
Assuntos
Infecções por Birnaviridae/imunologia , Vírus da Doença Infecciosa da Bursa/imunologia , Proteínas com Motivo Tripartido/imunologia , Proteínas Estruturais Virais/metabolismo , Replicação Viral/imunologia , Animais , Galinhas , Proteínas com Motivo Tripartido/metabolismo , UbiquitinaçãoRESUMO
The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and -independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEAD-box helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25's catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-ß production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence.
Assuntos
Antivirais/imunologia , Proteína DEAD-box 58/imunologia , RNA Helicases DEAD-box/imunologia , Imunidade/imunologia , Receptores Imunológicos/imunologia , Fatores de Transcrição/imunologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Linhagem Celular , Regulação da Expressão Gênica/imunologia , Células HEK293 , Humanos , Vírus da Influenza A/imunologia , Interferons/imunologia , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/imunologia , Transdução de Sinais/imunologia , Ubiquitinação/imunologiaRESUMO
A weak production of INF-ß along with an exacerbated release of pro-inflammatory cytokines have been reported during infection by the novel SARS-CoV-2 virus. SARS-CoV-2 encodes several proteins able to counteract the host immune system, which is believed to be one of the most important features contributing to the viral pathogenesis and development of a severe clinical picture. Previous reports have demonstrated that SARS-CoV-2 N protein, along with some non-structural and accessory proteins, efficiently suppresses INF-ß production by interacting with RIG-I, an important pattern recognition receptor (PRR) involved in the recognition of pathogen-derived molecules. In the present study, we better characterized the mechanism by which the SARS-CoV-2 N counteracts INF-ß secretion and affects RIG-I signaling pathways. In detail, when the N protein was ectopically expressed, we noted a marked decrease in TRIM25-mediated RIG-I activation. The capability of the N protein to bind to, and probably mask, TRIM25 could be the consequence of its antagonistic activity. Furthermore, this interaction occurred at the SPRY domain of TRIM25, harboring the RNA-binding activity necessary for TRIM25 self-activation. Here, we describe new findings regarding the interplay between SARS-CoV-2 and the IFN system, filling some gaps for a better understanding of the molecular mechanisms affecting the innate immune response in COVID-19.
Assuntos
COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Proteína DEAD-box 58/imunologia , Receptores Imunológicos/imunologia , SARS-CoV-2/imunologia , Fatores de Transcrição/imunologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , COVID-19/genética , COVID-19/virologia , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteína DEAD-box 58/genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Interferon beta/genética , Interferon beta/imunologia , Regiões Promotoras Genéticas , Receptores Imunológicos/genética , SARS-CoV-2/genética , Transdução de Sinais , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Macrophages have a variety of functions, such as secreting cytokines, phagocytosis, et al. Tripartite motif containing 59 (TRIM59) protein is highly expressed in tumor cells. It can regulate proliferation of tumor cells and promote tumor progression. Recent studies shown that the expression of TRIM59 was different in macrophages when stimulated by different stimuli, however, the effects of TRIM59 on macrophage gene expression profiles and functions are still unknown. In our study, we constructed RAW264.7 macrophages with high and low expression of TRIM59, and used next generation sequencing to explore the effects of TRIM59 on macrophage gene expression profiles. Results showed that TRIM59 affected an abundant number of genes, and may affect phagocytosis and cell cycles. We also examined the expression of surface molecules, secretion of cytokines, phagocytosis, proliferation, and apoptosis of macrophages, and confirmed that TRIM59 increased the expression of FcγRs CD16/32, CD64 and the secretion of TNF-α and IL-10, promoted phagocytosis and proliferation of RAW264.7 cells, inhibited the expression of complement receptor CD11b and antigen presentation related receptors (MHCII, CD80), but TRIM59 had no significant effect on apoptosis. Our study explored the effect of TRIM59 on the gene expression and function of macrophages comprehensively.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/imunologia , Animais , Antígenos CD/genética , Apoptose , Ciclo Celular , Proliferação de Células , Citocinas/imunologia , Camundongos , Fagocitose , Células RAW 264.7 , RNA Interferente Pequeno/genética , TranscriptomaRESUMO
Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.
Assuntos
Lisossomos/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Células Cultivadas , Humanos , Concentração de Íons de Hidrogênio , Doença Pulmonar Obstrutiva Crônica/patologiaRESUMO
Autophagy is a lysosomal-dependent degradative mechanism essential in maintaining cellular homeostasis, but it is also considered an ancient form of innate eukaryotic fighting against invading microorganisms. Mounting evidence has shown that HIV-1 is a critical target of autophagy that plays a role in HIV-1 replication and disease progression. In a special subset of HIV-1-infected patients that spontaneously and durably maintain extremely low viral replication, namely, long-term nonprogressors (LTNP), the resistance to HIV-1-induced pathogenesis is accompanied, in vivo, by a significant increase in the autophagic activity in peripheral blood mononuclear cells. Recently, a new player in the battle of autophagy against HIV-1 has been identified, namely, tripartite motif protein 5α (TRIM5α). In vitro data demonstrated that TRIM5α directly recognizes HIV-1 and targets it for autophagic destruction, thus protecting cells against HIV-1 infection. In this paper, we analyzed the involvement of this factor in the control of HIV-1 infection through autophagy, in vivo, in LTNP. The results obtained showed significantly higher levels of TRIM5α expression in cells from LTNP with respect to HIV-1-infected normal progressor patients. Interestingly, the colocalization of TRIM5α and HIV-1 proteins in autophagic vacuoles in LTNP cells suggested the participation of TRIM5α in the autophagy containment of HIV-1 in LTNP. Altogether, our results point to a protective role of TRIM5α in the successful control of the chronic viral infection in HIV-1-controllers through the autophagy mechanism. In our opinion, these findings could be relevant in fighting against HIV-1 disease, because autophagy inducers might be employed in combination with antiretroviral drugs.
Assuntos
Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Replicação Viral , Adulto , Idoso , Fatores de Restrição Antivirais , Autofagia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Accumulating evidence has shown that long noncoding RNAs (lncRNAs) are involved in several biological processes, including immune responses. However, the role of lncRNAs in antiviral innate immune responses remains largely elusive. Here, we identify an uncharacterized human lncRNA AVAN from influenza A virus (IAV) infected patients, that is significantly upregulated following RNA virus infection. During IAV infection, AVAN play an indispensable role in antiviral immune responses. In vivo, we enforced the expression of AVAN in transgenic mice or adeno-associated virus encoding AVAN delivery system and found that AVAN significantly alleviated IAV virulence and virus replication. Mechanistically, nuclear AVAN positively regulates the transcription of forkhead box O3A (FOXO3a) by associating with its promoter and inducing chromatin remodeling to promote neutrophil chemotaxis. Meanwhile, cytoplasmic AVAN binds directly to the E3 ligase TRIM25 and enhances TRIM25-mediated K63-linked ubiquitination of RIG-I, thereby promoting TRIM25- and RIG-I-mediated antiviral innate immune responses, including the induction of type I interferon and ISGs. Moreover, AVAN binds to the B Box/CCD domain of TRIM25 and 1-200nt of AVAN were the functional moieties. Collectively, our findings highlight the potential clinical implications of human lncRNA AVAN as a key positive regulator of the antiviral innate immune response and a promising target for developing broad antiviral therapeutics.
Assuntos
Proteínas de Ligação a DNA/imunologia , Proteína Forkhead Box O3/imunologia , RNA Longo não Codificante/imunologia , Fatores de Transcrição/imunologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Células A549 , Animais , Feminino , Proteína Forkhead Box O3/genética , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Longo não Codificante/genética , Transdução de Sinais/imunologia , Transcrição Gênica , Regulação para CimaRESUMO
An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions of individuals and is still infecting over a million people every year. To counteract retroviruses such as this, primates including humans have evolved an innate immune sensor for the retroviral capsid lattice known as TRIM5α. Although the molecular basis for its ability to restrict retroviruses is debated, it is currently accepted that TRIM5α forms higher-order assemblies around the incoming retroviral capsid that are not only disruptive for the virus lifecycle, but also trigger the activation of an antiviral state. More recently, it was discovered that TRIM5α restriction is broader than previously thought because it restricts not only the human retroelement LINE-1, but also the tick-borne flaviviruses, an emergent group of RNA viruses that have vastly different strategies for replication compared to retroviruses. This review focuses on the underlying mechanisms of TRIM5α-mediated restriction of retroelements and flaviviruses and how they differ from the more widely known ability of TRIM5α to restrict retroviruses.
Assuntos
Capsídeo/imunologia , Imunidade Inata , Vírus de RNA/imunologia , Vírus de RNA/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Fatores de Restrição Antivirais , Capsídeo/metabolismo , Proteínas de Transporte/genética , Flavivirus/imunologia , Flavivirus/metabolismo , Humanos , Vírus de RNA/classificação , Vírus de RNA/genética , Retroviridae/imunologia , Retroviridae/metabolismo , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/prevenção & controle , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologiaRESUMO
Human immunodeficiency virus-1 (HIV-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. Combination antiretroviral treatment is highly effective, but HIV-1 patients that have been treated still suffer from chronic inflammation and residual viral replication. It is therefore paramount to identify therapeutically efficacious strategies to eradicate viral reservoirs and ultimately develop a cure for HIV-1. It has been long accepted that the restriction factor tripartite motif protein 5 isoform alpha (TRIM5α) restricts HIV-1 infection in a species-specific manner, with rhesus macaque TRIM5α strongly restricting HIV-1, and human TRIM5α having a minimal restriction capacity. However, several recent studies underscore human TRIM5α as a cell-dependent HIV-1 restriction factor. Here, we present an overview of the latest research on human TRIM5α and propose a novel conceptualization of TRIM5α as a restriction factor with a varied portfolio of antiviral functions, including mediating HIV-1 degradation through autophagy- and proteasome-mediated mechanisms, and acting as a viral sensor and effector of antiviral signaling. We have also expanded on the protective antiviral roles of autophagy and outline the therapeutic potential of autophagy modulation to intervene in chronic HIV-1 infection.
Assuntos
Autofagia , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , HIV-1/fisiologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Fatores de Restrição Antivirais , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Replicação ViralRESUMO
Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA viruses. This study shows that TRIM22 has an additional intrinsic role against DNA viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of the ß- and γ- herpesviruses. Allelic variants in TRIM22 showed different degrees of anti-herpesviral activity; thus, TRIM22 genetic variability may contribute to the varying susceptibility to HSV-1 infection in humans. Collectively, these results argue that TRIM22 is a novel restriction factor and expand the list of restriction factors functioning in the infected cell nucleus to counter DNA virus infection.
Assuntos
Epigênese Genética , Inativação Gênica , Genes Precoces , Herpesvirus Humano 1/fisiologia , Antígenos de Histocompatibilidade Menor/fisiologia , Proteínas Repressoras/fisiologia , Proteínas com Motivo Tripartido/fisiologia , Linhagem Celular , Suscetibilidade a Doenças/imunologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Heterocromatina/metabolismo , Histonas/metabolismo , Humanos , Antígenos de Histocompatibilidade Menor/imunologia , Proteínas Repressoras/imunologia , Proteínas com Motivo Tripartido/imunologia , Replicação Viral/genéticaRESUMO
The aim of this study is to identify novel tumor-associated antigens (TAAs) of lung cancer by using serological analysis of recombinant cDNA expression library (SEREX) and bioinformatics analysis as well as to explore their humoral immune response. SEREX and pathway enrichment analysis were used to immunoscreen TAAs of lung cancer and elaborate their function in biological pathways, respectively. Subsequently, the sera level of autoantibodies against the selected TAAs (TOP2A, TRIM37, HSP90AB1, EEF1G and TPP1) was detected by immunoserological analysis to explore the immune response of these antigens. The Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) database were applied to explore the mRNA and protein expression level of TOP2A, TRIM37 and HSP90AB1 in tissues, respectively. Seventy positive clones were identified by SEREX which contain 63 different genes, and 35 genes of them have been reported. These 35 genes were mainly related to regulation of different transcription factor and performed enrichment in legionellosis, RNA transport, IL-17 signaling pathway via enrichment analysis. Additionally, the positive rate of autoantibodies against TOP2A, TRIM37 and HSP90AB1 in lung cancer patients were typically higher than normal control (NC; P < 0.05). Moreover, the combination of the autoantibodies against TOP2A, TRIM37 and HSP90AB1 possessed an excellent diagnostic performance with sensitivity of 84% and specificity of 60%. The mRNA expression level of TOP2A was obviously unregulated in squamous cell carcinoma (SCC) tissues and adenocarcinoma (ADC) tissues compared to normal tissues (P < 0.05). In addition, TRIM37 and HSP90AB1 also showed a significant difference between SCC and NC at the mRNA expression level (P < 0.05). This study combining comprehensive autoantibody and gene expression assays has added to the growing list of lung cancer antigens, which may aid the development of diagnostic and immunotherapeutic targets for lung cancer patients.
Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Testes Sorológicos/métodos , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adulto , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Estudos de Casos e Controles , Biologia Computacional , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/imunologia , Conjuntos de Dados como Assunto , Diagnóstico Diferencial , Feminino , Perfilação da Expressão Gênica , Biblioteca Gênica , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/imunologia , Voluntários Saudáveis , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/imunologia , Sensibilidade e Especificidade , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/imunologia , Tripeptidil-Peptidase 1 , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Adulto JovemRESUMO
The ubiquitin-proteasome system, which is one of the systems for cell protein homeostasis and degradation, happens through the ordered and coordinated action of three types of enzymes, E1 ubiquitin-activating enzyme, E2 ubiquitin-carrier enzyme, E3 ubiquitin-protein ligase. Tripartite motif-containing (TRIM) family proteins are the richest subfamily of really interesting new gene E3 ubiquitin ligases, which play a critical role not only in many biological processes, including proliferation, apoptosis, pyroptosis, innate immunity, and autophagy, but also many diseases like cancer, diabetes mellitus, and neurodegenerative disease. Increasing evidence suggests that TRIM family proteins play a vital role in modulating autophagy, pyroptosis, and diabetes mellitus. The aim of this review is to discuss the role of TRIM proteins in the regulation of autophagy, pyroptosis, diabetes mellitus, and diabetic complications.
Assuntos
Proteínas com Motivo Tripartido/imunologia , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/fisiologia , Autofagia/fisiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Homeostase , Humanos , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios Proteicos , Piroptose/fisiologia , Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologiaRESUMO
Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory tract disease. Although RSV causes major economic losses every year, effective treatments have not been found so far. Recent studies have shown that the tripartite motif-containing (TRIM) superfamily plays an essential role in the immune response. In this study, we found that TRIM22 had an inhibitory effect on RSV infection, and downregulation of TRIM22 moderately enhanced RSV replication. Our data further demonstrated that RSV infection induced TRIM22 expression through the activation of JAK-STAT1/2 signaling. RSV infection also induced TRIM22 expression. Taken together, these data points showed that the TRIM family member, TRIM22, had an essential role in resisting RSV infection, and this effect was closely related to the JAK-STAT1/2 pathway. Our results provide promising evidence for a novel target for the prevention and treatment of RSV.
Assuntos
Janus Quinases/genética , Antígenos de Histocompatibilidade Menor/genética , Proteínas Repressoras/genética , Vírus Sincicial Respiratório Humano/fisiologia , Fator de Transcrição STAT1/genética , Transdução de Sinais , Proteínas com Motivo Tripartido/genética , Replicação Viral/genética , Células A549 , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Janus Quinases/metabolismo , Antígenos de Histocompatibilidade Menor/imunologia , Proteínas Repressoras/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Fator de Transcrição STAT1/metabolismo , Proteínas com Motivo Tripartido/imunologia , Replicação Viral/imunologiaRESUMO
TRIM (Tripartite motif) and TRIM-like proteins have emerged as an important class of E3 ligases in innate immunity. Their functions range from activation or regulation of innate immune signaling pathway to direct detection and restriction of pathogens. Despite the importance, molecular mechanisms for many TRIM/TRIM-like proteins remain poorly characterized, in part due to challenges of identifying their substrates. In this review, we discuss several TRIM/TRIM-like proteins in RNA sensing pathways and viral restriction functions. We focus on those containing PRY-SPRY, the domain most frequently used for substrate recognition, and discuss emerging mechanisms that are commonly utilized by several TRIM/TRIM-like proteins to tightly control their interaction with the substrates.
Assuntos
Domínio B30.2-SPRY/genética , Proteína DEAD-box 58/genética , Imunidade Inata , Helicase IFIH1 Induzida por Interferon/genética , Receptores Imunológicos/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteína DEAD-box 58/imunologia , Regulação da Expressão Gênica , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Família Multigênica , Receptores Imunológicos/imunologia , Transdução de Sinais , Especificidade por Substrato , Proteínas com Motivo Tripartido/química , Proteínas com Motivo Tripartido/classificação , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/classificação , Ubiquitina-Proteína Ligases/imunologiaRESUMO
Tripartite motif (TRIM) family proteins are named by the presence of tripartite motifs in their amino terminal domains. Apart from the amino terminal, their carboxyl terminal contain variable domains which mediate diverse functions of the TRIM proteins. It had been found that TRIM proteins played important roles in distinct biological processes, such as innate immunity, anti-tumor immunity, cell cycle regulation and so on. In the present study, we cloned a TRIM32 (LvTRIM32) gene from Litopenaeus vannamei. LvTRIM32 was highly expressed in hemocytes, gills and epidermis, and subcellular localization analysis indicated that it was widely distributed in S2 cells. In vitro ubiquitination assays indicated that LvTRIM32 had E3 ubiquitin ligase activity. Results of real-time RT-PCR assay showed that LvTRIM32 was induced in shrimp hemocytes upon oxidative stress. It was also proved that the promoter activity of LvTRIM32 was enhanced by NF-E2-related factor, and knocked-down expression of LvTRIM32 depressed the expression of malic enzyme and epoxide hydrolase. Downregulated LvTRIM32 suppressed the cumulative mortality of shrimp under oxidative stress. Moreover, it was found that LvTRIM32 could be induced in shrimp hemocytes upon immunostimulation, and downregulated LvTRIM32 increased the cumulative mortality of shrimp infected with white spot syndrome virus (WSSV) or Vibrio alginolyticus. Collecting results suggested that LvTRIM32 was a member of shrimp antioxidant stress system, and it was also involved in WSSV- or V. alginolyticus-infection resistance.
Assuntos
Proteínas de Artrópodes/genética , Imunidade Inata/genética , Estresse Oxidativo/genética , Penaeidae/genética , Penaeidae/imunologia , Proteínas com Motivo Tripartido/genética , Vírus da Síndrome da Mancha Branca 1/fisiologia , Animais , Proteínas de Artrópodes/imunologia , Proteínas de Artrópodes/metabolismo , Perfilação da Expressão Gênica , Hemócitos/imunologia , Proteínas com Motivo Tripartido/imunologia , Proteínas com Motivo Tripartido/metabolismoRESUMO
INTRODUCTION: The tripartite motif (TRIM) plays various roles in pathological and physiological functions, including neurological diseases, genetic disorders, carcinogenesis, innate immune signaling, and antiviral activity. TRIM56 is a cytoplasmic protein whose expression is stimulated by type I interferon and may function as an antiviral agent. Here, the authors conducted a systematic search on papers that reported antiviral effects of TRIM56. AREAS COVERED: The authors conducted a comprehensive search of the PubMed database without time or language limitation, after using the Medical Subject Headings (MeSH) Database terms. Initially, a structured search and full article review yielded 31 papers. Relevant original and review articles on TRIM56 were included. The reference lists were then reviewed, and the cited articles were added. Expert opinion: TRIM56 has been shown to have direct antiviral actions against positive-sense single-stranded RNA viruses from the families Flaviviridae, Coronaviridae, and Retroviridae. Moreover, it may be effective against negative-sense single-strand RNA viruses from the families Paramyxoviridae and Orthomyxoviridae, as well as a DNA virus, Herpes simplex virus 1 (HSV-1). These studies could suggest the potential of a TRIM56-based antiviral against COVID-19 from the family Coronaviridae, containing single-stranded positive-sense RNA genome. However, its efficacy and antiviral mechanisms need to be further examined.