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1.
J Clin Invest ; 134(16)2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39145453

RESUMO

Autoimmune diseases are commonly associated with a polygenic inheritance pattern. In rare instances, causal monogenic variants have been identified. The study by Liu et al. in this issue of the JCI provides an example of monogenic variants occurring in patients with IgG4-related disease (IgG4-RD). The authors investigated a familial cluster of IgG4-RD that consisted of an affected father and two daughters; the mother was unaffected. Genome sequencing of this quad identified a variant in IKZF1 (encoding IKAROS) and another variant in UBR4 (encoding E3 ubiquitin ligase). Both variants were present in the father and both daughters but absent in the unaffected mother. Using multidimensional profiling of immune cells and functional experiments in primary cells, the authors determined a molecular pathway contributing to T cell activation in IgG4-RD. Importantly, the characterization of these variants provides insights into pathogenic mechanisms in IgG4-RD and, potentially, other autoimmune diseases.


Assuntos
Fator de Transcrição Ikaros , Doença Relacionada a Imunoglobulina G4 , Ubiquitina-Proteína Ligases , Humanos , Doença Relacionada a Imunoglobulina G4/genética , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Feminino , Masculino , Imunoglobulina G/imunologia , Imunoglobulina G/genética , Linfócitos T/imunologia , Linfócitos T/patologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Variação Genética
2.
J Immunol ; 213(2): 187-203, 2024 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-38829131

RESUMO

The RING finger (RNF) family, a group of E3 ubiquitin ligases, plays multiple essential roles in the regulation of innate immunity and resistance to viral infection in mammals. However, it is still unclear whether RNF proteins affect the production of IFN-I and the replication of avian influenza virus (AIV) in ducks. In this article, we found that duck RNF216 (duRNF216) inhibited the duRIG-I signaling pathway. Conversely, duRNF216 deficiency enhanced innate immune responses in duck embryonic fibroblasts. duRNF216 did not interacted with duRIG-I, duMDA5, duMAVS, duSTING, duTBK1, or duIRF7 in the duck RIG-I pathway. However, duRNF216 targeted duTRAF3 and inhibited duMAVS in the recruitment of duTRAF3 in a dose-dependent manner. duRNF216 catalyzed K48-linked polyubiquitination of duck TRAF3, which was degraded by the proteasome pathway. Additionally, AIV PB1 protein competed with duTRAF3 for binding to duRNF216 to reduce degradation of TRAF3 by proteasomes in the cytoplasm, thereby slightly weakening duRNF216-mediated downregulation of IFN-I. Moreover, although duRNF216 downregulated the IFN-ß expression during virus infection, the expression level of IFN-ß in AIV-infected duck embryonic fibroblasts overexpressing duRNF216 was still higher than that in uninfected cells, which would hinder the viral replication. During AIV infection, duRNF216 protein targeted the core protein PB1 of viral polymerase to hinder viral polymerase activity and viral RNA synthesis in the nucleus, ultimately strongly restricting viral replication. Thus, our study reveals a new mechanism by which duRNF216 downregulates innate immunity and inhibits AIV replication in ducks. These findings broaden our understanding of the mechanisms by which the duRNF216 protein affects AIV replication in ducks.


Assuntos
Patos , Imunidade Inata , Virus da Influenza A Subtipo H5N1 , Influenza Aviária , Transdução de Sinais , Ubiquitina-Proteína Ligases , Replicação Viral , Animais , Patos/imunologia , Patos/virologia , Replicação Viral/imunologia , Transdução de Sinais/imunologia , Influenza Aviária/imunologia , Influenza Aviária/virologia , Virus da Influenza A Subtipo H5N1/imunologia , Virus da Influenza A Subtipo H5N1/fisiologia , Imunidade Inata/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Fibroblastos/imunologia , Fibroblastos/virologia , Proteínas Aviárias/imunologia , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Ubiquitinação , Proteína DEAD-box 58/metabolismo , Proteína DEAD-box 58/imunologia
3.
J Clin Invest ; 134(16)2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38885295

RESUMO

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.


Assuntos
Autoimunidade , Fator de Transcrição Ikaros , Células Th2 , Ubiquitina-Proteína Ligases , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Autoimunidade/genética , Células Th2/imunologia , Células Th2/patologia , Feminino , Masculino , Doença Relacionada a Imunoglobulina G4/genética , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-fyn/imunologia , Linhagem
4.
Proc Natl Acad Sci U S A ; 120(52): e2308853120, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38109536

RESUMO

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.


Assuntos
Esclerose Lateral Amiotrófica , Ubiquitina-Proteína Ligases , Animais , Camundongos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/imunologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Imunidade Inata/genética , Nucleotidiltransferases/metabolismo , Proteólise , Transdução de Sinais/fisiologia , Modelos Animais de Doenças , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/imunologia , Ubiquitina-Proteína Ligases/metabolismo
5.
Front Cell Infect Microbiol ; 13: 1256882, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37719674

RESUMO

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/imunologia
6.
J Virol ; 97(4): e0009523, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37014223

RESUMO

Many RING domain E3 ubiquitin ligases play critical roles in fine-tuning the innate immune response, yet little is known about their regulatory role in flavivirus-induced innate immunity. In previous studies, we found that the suppressor of cytokine signaling 1 (SOCS1) protein mainly undergoes lysine 48 (K48)-linked ubiquitination. However, the E3 ubiquitin ligase that promotes the K48-linked ubiquitination of SOCS1 is unknown. In the present study, we found that RING finger protein 123 (RNF123) binds to the SH2 domain of SOCS1 through its RING domain and facilitates the K48-linked ubiquitination of the K114 and K137 residues of SOCS1. Further studies found that RNF123 promoted the proteasomal degradation of SOCS1 and promoted Toll-like receptor 3 (TLR3)- and interferon (IFN) regulatory factor 7 (IRF7)-mediated type I IFN production during duck Tembusu virus (DTMUV) infection through SOCS1, ultimately inhibiting DTMUV replication. Overall, these findings demonstrate a novel mechanism by which RNF123 regulates type I IFN signaling during DTMUV infection by targeting SOCS1 degradation. IMPORTANCE In recent years, posttranslational modification (PTM) has gradually become a research hot spot in the field of innate immunity regulation, and ubiquitination is one of the critical PTMs. DTMUV has seriously endangered the development of the waterfowl industry in Southeast Asian countries since its outbreak in 2009. Previous studies have shown that SOCS1 is modified by K48-linked ubiquitination during DTMUV infection, but E3 ubiquitin ligase catalyzing the ubiquitination of SOCS1 has not been reported. Here, we identify for the first time that RNF123 acts as an E3 ubiquitin ligase that regulates TLR3- and IRF7-induced type I IFN signaling during DTMUV infection by targeting the K48-linked ubiquitination of the K114 and K137 residues of SOCS1 and the proteasomal degradation of SOCS1.


Assuntos
Infecções por Flavivirus , Flavivirus , Interferon Tipo I , Proteína 1 Supressora da Sinalização de Citocina , Animais , Patos , Flavivirus/fisiologia , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Receptor 3 Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação , Proteína 1 Supressora da Sinalização de Citocina/imunologia , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/virologia , Ligação Proteica , Domínios Proteicos/imunologia , Replicação Viral , Células HEK293 , Embrião de Mamíferos , Humanos
7.
Front Immunol ; 14: 1324516, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38250078

RESUMO

RNF5 is an E3 ubiquitin ligase involved in various physiological processes such as protein localization and cancer progression. Recent studies have shown that RNF5 significantly inhibits antiviral innate immunity by promoting the ubiquitination and degradation of STING and MAVS, which are essential adaptor proteins, as well as their downstream signal IRF3. The abundance of RNF5 is delicately regulated by both host factors and viruses. Host factors have been found to restrict RNF5-mediated ubiquitination, maintaining the stability of STING or MAVS through distinct mechanisms. Meanwhile, viruses have developed ingenious strategies to hijack RNF5 to ubiquitinate and degrade immune proteins. Moreover, recent studies have revealed the multifaceted roles of RNF5 in the life cycle of various viruses, including SARS-CoV-2 and KSHV. Based on these emerging discoveries, RNF5 represents a novel means of modulating antiviral immunity. In this review, we summarize the latest research on the roles of RNF5 in antiviral immunity and virus life cycle. This comprehensive understanding could offer valuable insights into exploring potential therapeutic applications focused on targeting RNF5 during viral infections.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Imunidade Inata , Ubiquitina-Proteína Ligases , Viroses , Transporte Proteico , Viroses/imunologia , Ubiquitina-Proteína Ligases/imunologia
8.
Nature ; 610(7930): 182-189, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36131013

RESUMO

Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras1 (PROTACs), have highlighted clinically important advantages of target degradation over inhibition2. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required3. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for 'on-demand' degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.


Assuntos
Anticorpos , Especificidade de Anticorpos , Proteínas de Membrana , Proteólise , Ubiquitina-Proteína Ligases , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Neoplasias Colorretais/metabolismo , Ligantes , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Especificidade por Substrato , Ubiquitina-Proteína Ligases/imunologia , Ubiquitina-Proteína Ligases/metabolismo
9.
PLoS Pathog ; 18(5): e1010544, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35584187

RESUMO

Pseudorabies virus (PRV) has evolved various immune evasion mechanisms that target host antiviral immune responses. However, it is unclear whether and how PRV encoded proteins modulate the cGAS-STING axis for immune evasion. Here, we show that PRV tegument protein UL13 inhibits STING-mediated antiviral signaling via regulation of STING stability. Mechanistically, UL13 interacts with the CDN domain of STING and recruits the E3 ligase RING-finger protein 5 (RNF5) to promote K27-/K29-linked ubiquitination and degradation of STING. Consequently, deficiency of RNF5 enhances host antiviral immune responses triggered by PRV infection. In addition, mutant PRV lacking UL13 impaired in antagonism of STING-mediated production of type I IFNs and shows attenuated pathogenicity in mice. Our findings suggest that PRV UL13 functions as an antagonist of IFN signaling via a novel mechanism by targeting STING to persistently evade host antiviral responses.


Assuntos
Herpesvirus Suídeo 1 , Proteínas de Membrana , Proteínas Quinases , Pseudorraiva , Ubiquitina-Proteína Ligases , Animais , Herpesvirus Suídeo 1/imunologia , Imunidade Inata , Proteínas de Membrana/imunologia , Camundongos , Proteínas Quinases/imunologia , Pseudorraiva/imunologia , Ubiquitina-Proteína Ligases/imunologia , Proteínas Virais/imunologia
10.
J Immunol ; 208(8): 2067-2076, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35365564

RESUMO

The E3 ubiquitin ligase Riplet mediates retinoic acid-inducible gene-I polyubiquitination and is essential for viral-induced expression of type I IFNs in dendritic cells and macrophages. The function of Riplet in innate immunity has been well demonstrated; however, its role in adaptive immunity during the antitumor immune response is unclear. In this study, we examined the role of Riplet in the T cell-mediated antitumor immune response. Riplet was expressed in T cells and upregulated in CD8+ T cells in response to TCR-mediated stimulation. Furthermore, PR domain containing 1, eomesodermin, and killer cell lectin-like receptor G1 expression was increased in effector CD8+ T cells by Riplet knockout in vitro, which suggests that Riplet is involved in the effector function of CD8+ T cells. Our results indicated that Riplet deficiency augmented the antitumor response of MO4 (OVA-expressing melanoma)-bearing mice treated with OVA peptide-pulsed dendritic cells. Moreover, both CD4+ and CD8+ T cells played important roles in Riplet-mediated augmentation of the antitumor immune response. In tumor-draining lymph nodes, the Th1 response was promoted, and the induction of OVA-specific CD8+ T cells and IFN-γ production were enhanced by Riplet deficiency. Furthermore, the IFN-γ response and OVA-specific cytotoxicity of CD8+ T cells in tumor tissue were augmented by Riplet deficiency. The expression of Cxcl9fluorescence-minus-one and Cxcl10 mRNA was also enhanced in the tumor microenvironment by Riplet knockout, consistent with the augmented recruitment of CTLs. Overall, we clarified a function of Riplet in T cells, which is to suppress the antitumor immune response through modulating Th1 and CTLs.


Assuntos
Imunidade Adaptativa , Linfócitos T , Ubiquitina-Proteína Ligases , Imunidade Adaptativa/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitina-Proteína Ligases/imunologia
11.
Front Immunol ; 13: 845193, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154166

RESUMO

N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m6A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m6A modifications in the 3'UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that in vitro and in vivo Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1-regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.


Assuntos
Antígeno B7-H1/imunologia , Colangiocarcinoma/imunologia , Proteínas Nucleares/imunologia , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/imunologia , Adenosina/análogos & derivados , Adenosina/imunologia , Linhagem Celular , Colangiocarcinoma/terapia , Humanos , Imunoterapia , Metiltransferases/imunologia , RNA Mensageiro/imunologia
12.
Am J Hum Genet ; 109(2): 361-372, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35051358

RESUMO

Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.


Assuntos
Proteína BRCA1/genética , Mutação em Linhagem Germinativa , Mutação com Perda de Função , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adolescente , Proteína BRCA1/imunologia , Criança , Pré-Escolar , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/imunologia , Família , Feminino , Regulação da Expressão Gênica , Heterozigoto , Histonas/genética , Histonas/imunologia , Fator C1 de Célula Hospedeira/genética , Fator C1 de Célula Hospedeira/imunologia , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/patologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/imunologia , Ubiquitina/genética , Ubiquitina/imunologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação
13.
New Phytol ; 233(5): 2249-2265, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34918346

RESUMO

Plants use pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and activate pattern-triggered immunity (PTI). Precise regulation of information from PRRs to downstream signaling components is vital to mounting an appropriate immune response and requires dynamic interactions of these PTI components. We used transcriptome profiling, phenotypic analysis, molecular genetics, and protein-protein interaction analysis to understand the roles of the Arabidopsis plant U-box (PUB) proteins PUB2 and PUB4 in disease resistance and PTI signaling. Loss of function of both PUB2 and PUB4 diminishes the PAMP-triggered oxidative bursts and dampens mitogen-activated protein kinase signaling, resulting in a severe compromise in resistance to not only pathogenic but also nonpathogenic strains of Pseudomonas syringae. Within PUB4, the E3 ligase activity is dispensable, but the armadillo repeat region is essential and sufficient for its function in immunity. PUB2 and PUB4 interact with PTI signaling components, including FLS2, BIK1, PBL27, and RbohD, and enhance FLS2-BIK1 and BIK1-RbohD interactions. Our study reveals that PUB2 and PUB4 are critical components of plant immunity and connect PTI components to positively regulate defense responses.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Doenças das Plantas , Ubiquitina-Proteína Ligases , Arabidopsis/imunologia , Proteínas de Arabidopsis/imunologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal , Pseudomonas syringae/fisiologia , Ubiquitina-Proteína Ligases/imunologia
14.
Front Immunol ; 12: 740223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956175

RESUMO

Poxviruses have evolved a variety of innate immunity evasion mechanisms, some of which involve poxvirus-encoded E3 ubiquitin ligases and adaptor proteins. Based on their functional domains and ubiquitin transfer mechanisms, these poxvirus-encoded E3 ubiquitin ligases and adaptor proteins can be divided into five categories: PRANC, ANK/BC, BBK, P28/RING, and MARCH proteins. Although the substrates of many poxvirus E3 ubiquitin ligases remain to be discovered, most of the identified substrates are components of the innate immune system. In this review, we discuss the current research progress on poxvirus-encoded E3 ubiquitin ligases and adaptor proteins to provide mechanistic insights into the interplay between these viruses and their hosts.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Poxviridae/enzimologia , Ubiquitina-Proteína Ligases/imunologia , Proteínas Virais/imunologia , Humanos , Poxviridae/imunologia
15.
Front Immunol ; 12: 769167, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956195

RESUMO

Inflammatory bowel disease (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), exhibits a complex multifactorial pathogenesis involving genetic susceptibility, imbalance of gut microbiota, mucosal immune disorder and environmental factors. Recent studies reported associations between ubiquitination and deubiquitination and the occurrence and development of inflammatory bowel disease. Ubiquitination modification, one of the most important types of post-translational modifications, is a multi-step enzymatic process involved in the regulation of various physiological processes of cells, including cell cycle progression, cell differentiation, apoptosis, and innate and adaptive immune responses. Alterations in ubiquitination and deubiquitination can lead to various diseases, including IBD. Here, we review the role of E3 ubiquitin ligases and deubiquitinases (DUBs) and their mediated ubiquitination and deubiquitination modifications in the pathogenesis of IBD. We highlight the importance of this type of posttranslational modification in the development of inflammation, and provide guidance for the future development of targeted therapeutics in IBD.


Assuntos
Enzimas Desubiquitinantes/imunologia , Doenças Inflamatórias Intestinais/imunologia , Processamento de Proteína Pós-Traducional/imunologia , Transdução de Sinais/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação/imunologia , Imunidade Adaptativa/imunologia , Colite Ulcerativa/enzimologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Doença de Crohn/enzimologia , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Enzimas Desubiquitinantes/metabolismo , Humanos , Imunidade Inata/imunologia , Inflamação/enzimologia , Inflamação/imunologia , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/enzimologia , Doenças Inflamatórias Intestinais/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
16.
Front Immunol ; 12: 749794, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721419

RESUMO

Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins-a post-translational modification that is essential for NF-κB activation. Human germline pathogenic variants that dysregulate linear ubiquitination and NF-κB signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers, systemic inflammation and enteropathy. We previously identified MALT1 paracaspase as a novel negative regulator of LUBAC by proteolytic cleavage of HOIL1. To directly investigate the impact of HOIL1 cleavage activity on the inflammatory response, we employed a stable transduction system to express and directly compare non-cleavable HOIL1 with wild-type HOIL1 in primary HOIL1-deficient patient skin fibroblasts. We discovered that non-cleavable HOIL1 resulted in enhanced NF-κB signaling in response to innate stimuli. Transcriptomics revealed enrichment of inflammation and proinflammatory cytokine-related pathways after stimulation. Multiplexed cytokine assays confirmed a 'hyperinflammatory' phenotype in these cells. This work highlights the physiological importance of MALT1-dependent cleavage and modulation of HOIL1 on NF-κB signaling and inflammation, provides a mechanism for the autoinflammation observed in MALT1-deficient patients, and will inform the development of therapeutics that target MALT1 paracaspase and LUBAC function in treating autoinflammatory skin diseases.


Assuntos
Fibroblastos/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , NF-kappa B/imunologia , Fatores de Transcrição/imunologia , Ubiquitina-Proteína Ligases/imunologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Transdução de Sinais , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética
17.
Nature ; 600(7887): 138-142, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34759314

RESUMO

Pathogens use virulence factors to inhibit the immune system1. The guard hypothesis2,3 postulates that hosts monitor (or 'guard') critical innate immune pathways such that their disruption by virulence factors provokes a secondary immune response1. Here we describe a 'self-guarded' immune pathway in human monocytes, in which guarding and guarded functions are combined in one protein. We find that this pathway is triggered by ICP0, a key virulence factor of herpes simplex virus type 1, resulting in robust induction of anti-viral type I interferon (IFN). Notably, induction of IFN by ICP0 is independent of canonical immune pathways and the IRF3 and IRF7 transcription factors. A CRISPR screen identified the ICP0 target MORC34 as an essential negative regulator of IFN. Loss of MORC3 recapitulates the IRF3- and IRF7-independent IFN response induced by ICP0. Mechanistically, ICP0 degrades MORC3, which leads to de-repression of a MORC3-regulated DNA element (MRE) adjacent to the IFNB1 locus. The MRE is required in cis for IFNB1 induction by the MORC3 pathway, but is not required for canonical IFN-inducing pathways. As well as repressing the MRE to regulate IFNB1, MORC3 is also a direct restriction factor of HSV-15. Our results thus suggest a model in which the primary anti-viral function of MORC3 is self-guarded by its secondary IFN-repressing function-thus, a virus that degrades MORC3 to avoid its primary anti-viral function will unleash the secondary anti-viral IFN response.


Assuntos
Adenosina Trifosfatases/imunologia , Proteínas de Ligação a DNA/imunologia , Modelos Imunológicos , Fatores de Virulência/imunologia , Adenosina Trifosfatases/deficiência , Adenosina Trifosfatases/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Edição de Genes , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Humanos , Proteínas Imediatamente Precoces/imunologia , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Monócitos/imunologia , Receptor de Interferon alfa e beta , Proteínas Repressoras/deficiência , Proteínas Repressoras/imunologia , Proteínas Repressoras/metabolismo , Elementos de Resposta/genética , Ubiquitina-Proteína Ligases/imunologia
18.
J Gen Virol ; 102(11)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34726593

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic etiological factor for Kaposi's sarcoma and primary effusion lymphoma in immunocompromised patients. KSHV utilizes two immune evasion E3 ubiquitin ligases, namely K3 and K5, to downregulate the expression of antigen-presenting molecules and ligands of natural killer (NK) cells in the host cells through an ubiquitin-dependent endocytic mechanism. This allows the infected cells to evade surveillance and elimination by cytotoxic lymphocytes and NK cells. The number of host cell molecular substrates reported for these ubiquitin ligases is limited. The identification of novel substrates for these ligases will aid in elucidating the mechanism underlying immune evasion of KSHV. This study demonstrated that K5 downregulated the cell surface expression of l-selectin, a C-type lectin-like adhesion receptor expressed in the lymphocytes. Tryptophan residue located at the centre of the E2-binding site in the K5 RINGv domain was essential to downregulate l-selectin expression. Additionally, the lysine residues located at the cytoplasmic tail of l-selectin were required for the K5-mediated downregulation of l-selectin. K5 promoted the degradation of l-selectin through polyubiquitination. These results suggest that K5 downregulates l-selectin expression on the cell surface by promoting polyubiquitination and ubiquitin-dependent endocytosis, which indicated that l-selectin is a novel substrate for K5. Additionally, K3 downregulated l-selectin expression. The findings of this study will aid in the elucidation of a novel immune evasion mechanism in KSHV.


Assuntos
Herpesvirus Humano 8/enzimologia , Proteínas Imediatamente Precoces/imunologia , Selectina L/genética , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/virologia , Ubiquitina-Proteína Ligases/imunologia , Proteínas Virais/imunologia , Regulação para Baixo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Imediatamente Precoces/genética , Evasão da Resposta Imune , Células Matadoras Naturais/imunologia , Selectina L/imunologia , Sarcoma de Kaposi/imunologia , Ubiquitina-Proteína Ligases/genética , Proteínas Virais/genética
19.
J Immunol ; 207(11): 2754-2769, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34759016

RESUMO

African swine fever is a severe animal infectious disease caused by African swine fever virus (ASFV), and the morbidity and mortality associated with virulent ASFV isolates are as high as 100%. Previous studies showed that the ability of ASFV to antagonize IFN production is closely related to its pathogenicity. Here, we report that ASFV HLJ/18 infection induced low levels of type I IFN and inhibited cGMP-AMP-induced type I IFN production in porcine alveolar macrophages that were isolated from specific pathogen-free Landrace piglets. Subsequently, an unbiased screen was performed to screen the ASFV genes with inhibitory effects on the type I IFN production. ASFV pI215L, a viral E2 ubiquitin-conjugating enzyme, was identified as one of the strongest inhibitory effectors on the production of type I IFN. Knockdown of pI215L expression inhibited ASFV replication and enhanced IFN-ß production. However, inhibition of type I IFN production by pI215L was independent of its E2 enzyme activity. Furthermore, we found that pI215L inhibited type I IFN production and K63-linked polyubiquitination of TANK-binding kinase 1 through pI215L-binding RING finger protein 138 (RNF138). ASFV pI215L enhanced the interaction between RNF138 and RNF128 and promoted RNF138 to degrade RNF128, which resulted in reduced K63-linked polyubiquitination of TANK-binding kinase 1 and type І IFN production. Taken together, our findings reveal a novel immune escape mechanism of ASFV, which provides a clue to the design and development of an immune-sensitive attenuated live vaccine.


Assuntos
Vírus da Febre Suína Africana/imunologia , Nucleotidiltransferases/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Ubiquitina-Proteína Ligases/imunologia , Células Cultivadas , Células HEK293 , Humanos , Transdução de Sinais/imunologia , Ubiquitinação
20.
Sci Immunol ; 6(64): eabh0707, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652961

RESUMO

Type 2 T helper (TH2) cells are protective against parasitic worm infections but also aggravate allergic inflammation. Although the role of dendritic cells (DCs) in TH2 cell differentiation is well established, the underlying mechanisms are largely unknown. Here, we show that DC induction of TH2 cells depends on membrane-associated RING-CH-1 (MARCH1) ubiquitin ligase. The pro-TH2 effect of MARCH1 relied on lymph node (LN)­resident DCs, which triggered T cell receptor (TCR) signaling and induced GATA-3 expression from naïve CD4+ T cells independent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of MHCII and CD86, the two substrates of MARCH1, failed to develop TH2 cells. These findings suggest that TH2 cell development depends on ubiquitin-mediated clearance of antigen-presenting and costimulatory molecules by LN-resident DCs and consequent control of TCR signaling.


Assuntos
Células Dendríticas/imunologia , Linfonodos/imunologia , Células Th2/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ubiquitina-Proteína Ligases/deficiência
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