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1.
Cells ; 10(12)2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34944095

RESUMO

Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.


Assuntos
Neoplasias/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Subunidades Proteicas/imunologia , Animais , Humanos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Subunidades Proteicas/química
2.
Cells ; 10(12)2021 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-34943847

RESUMO

Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.


Assuntos
Inflamação/sangue , Inflamação/imunologia , Complexo de Endopeptidases do Proteassoma/sangue , Complexo de Endopeptidases do Proteassoma/imunologia , Fatores Etários , Células Sanguíneas/enzimologia , Doença Crônica , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Sondas Moleculares/metabolismo , Fatores Sexuais
3.
Biomolecules ; 11(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34356615

RESUMO

The gut epithelial barrier provides the first line of defense protecting the internal milieu from the environment. To circumvent the exposure to constant challenges such as pathogenic infections and commensal bacteria, epithelial and immune cells at the gut barrier require rapid and efficient means to dynamically sense and respond to stimuli. Numerous studies have highlighted the importance of proteolysis in maintaining homeostasis and adapting to the dynamic changes of the conditions in the gut environment. Primarily, proteolytic activities that are involved in immune regulation and inflammation have been examined in the context of the lysosome and inflammasome activation. Yet, the key to cellular and tissue proteostasis is the ubiquitin-proteasome system, which tightly regulates fundamental aspects of inflammatory signaling and protein quality control to provide rapid responses and protect from the accumulation of proteotoxic damage. In this review, we discuss proteasome-dependent regulation of the gut and highlight the pathophysiological consequences of the disarray of proteasomal control in the gut, in the context of aberrant inflammatory disorders and tumorigenesis.


Assuntos
Mucosa Intestinal , Complexo de Endopeptidases do Proteassoma , Proteólise , Transdução de Sinais/imunologia , Animais , Ativação Enzimática/imunologia , Humanos , Inflamação/enzimologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/imunologia , Lisossomos/enzimologia , Lisossomos/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo
4.
Microbiol Res ; 250: 126810, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34246833

RESUMO

Plant pathogenic Gram-negative bacteria evade the host plant immune system by secreting Type III (T3E) and Type IV effector (T4E) proteins into the plant cytoplasm. Mostly T3Es are secreted into the plant cells to establish pathogenicity by affecting the vital plant process viz. metabolic pathways, signal transduction and hormonal regulation. Ubiquitin-26S proteasome system (UPS) exists as one of the important pathways in plants to control plant immunity and various cellular processes by employing several enzymes and enzyme components. Pathogenic and non-pathogenic bacteria are found to secrete effectors into plants with structural and/or functional similarity to UPS pathway components like ubiquitin E3 ligases, F-box domains, cysteine proteases, inhibitor of host UPS or its components, etc. The bacterial effectors mimic UPS components and target plant resistance proteins for degradation by proteasomes, thereby taking control over the host cellular activities as a strategy to exert virulence. Thus, the bacterial effectors circumvent plant cellular pathways leading to infection and disease development. This review highlights known bacterial T3E and T4E proteins that function and interfere with the ubiquitination pathway to regulate the immune system of plants.


Assuntos
Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Imunidade Vegetal , Plantas/microbiologia , Complexo de Endopeptidases do Proteassoma/imunologia , Ubiquitinação/imunologia , Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Plantas/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Ubiquitinação/genética
5.
Cells ; 10(7)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206607

RESUMO

The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.


Assuntos
Neoplasias Hematológicas/enzimologia , Neoplasias Hematológicas/imunologia , Hematopoese/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Neoplasias Hematológicas/tratamento farmacológico , Hematopoese/efeitos dos fármacos , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
6.
Sci Rep ; 11(1): 12666, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135356

RESUMO

Inactivated poultry vaccines are subject to routine potency testing for batch release, requiring large numbers of animals. The replacement of in vivo tests for cell-based alternatives can be facilitated by the identification of biomarkers for vaccine-induced immune responses. In this study, chicken bone marrow-derived dendritic cells were stimulated with an inactivated vaccine for infectious bronchitis virus and Newcastle disease virus, as well as inactivated infectious bronchitis virus only, and lipopolysaccharides as positive control, or left unstimulated for comparison with the stimulated samples. Next, the cells were lysed and subjected to proteomic analysis. Stimulation with the vaccine resulted in 66 differentially expressed proteins associated with mRNA translation, immune responses, lipid metabolism and the proteasome. For the eight most significantly upregulated proteins, mRNA expression levels were assessed. Markers that showed increased expression at both mRNA and protein levels included PLIN2 and PSMB1. Stimulation with infectious bronchitis virus only resulted in 25 differentially expressed proteins, which were mostly proteins containing Src homology 2 domains. Stimulation with lipopolysaccharides resulted in 118 differentially expressed proteins associated with dendritic cell maturation and antimicrobial activity. This study provides leads to a better understanding of the activation of dendritic cells by an inactivated poultry vaccine, and identified PLIN2 and PSMB1 as potential biomarkers for cell-based potency testing.


Assuntos
Células Dendríticas , Marcadores Genéticos/imunologia , Aves Domésticas/imunologia , Vacinas Virais , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Galinhas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Expressão Gênica/imunologia , Imunidade Inata , Vírus da Bronquite Infecciosa/imunologia , Doença de Newcastle/imunologia , Doença de Newcastle/prevenção & controle , Perilipina-2/imunologia , Perilipina-2/metabolismo , Aves Domésticas/genética , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/prevenção & controle , Doenças das Aves Domésticas/virologia , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteômica , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/farmacologia , Vacinas Virais/imunologia , Vacinas Virais/farmacologia
7.
Cells ; 10(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066177

RESUMO

Proteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the immune cells. Certain cells of the immune system are primary targets of retroviruses. It has been shown that several viral proteins directly affect proteasome functionality, while inhibition of proteasome activity with broad specificity proteasome inhibitors stimulates viral transduction. Here we specifically addressed the role of the immunoproteasomes during early stages of viral transduction and investigated the effects of specific immunoproteasome inhibition and activation prior to infection using a panel of cell lines. Inhibition of iPs in hematopoietic cells with immunoproteasome-specific inhibitor ONX-0914 resulted in increased infection by VSV-G pseudotyped lentiviruses. Moreover, a tendency for increased infection of cloned cells with endogenously decreased proteasome activity was revealed. Conversely, activation of iPs by IFN-γ markedly reduced the viral infectivity, which was rescued upon simultaneous immunoproteasome inhibition. Our results indicate that immunoproteasome activity might be determinative for the cellular antiretroviral resistance at least for the cells with high iP content. Finally, therapeutic application of immunoproteasome inhibitors might promote retroviral infection of cells in vivo.


Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Lentivirus , Complexo de Endopeptidases do Proteassoma/imunologia , Antirretrovirais/farmacologia , Bortezomib/farmacologia , Linhagem Celular , Citocinas/metabolismo , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Células HL-60 , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Oligopeptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Retroviridae , Células THP-1 , Células U937
8.
Nat Commun ; 12(1): 2713, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976225

RESUMO

Interleukin-1ß (IL-1ß) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1ß activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1ß is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1ß is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1ß cleavage by caspase-1. IL-1ß K133 is modified by ubiquitin and forms a salt bridge with IL-1ß D129. Loss of IL-1ß K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1ß. Accordingly, Il1bK133R/K133R mice have increased levels of precursor IL-1ß upon inflammasome priming and increased production of bioactive IL-1ß, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1ß activity and safeguard against damaging inflammation.


Assuntos
Caspase 1/genética , Inflamassomos/genética , Interleucina-1beta/genética , Complexo de Endopeptidases do Proteassoma/genética , Processamento de Proteína Pós-Traducional , Animais , Caspase 1/imunologia , Células HEK293 , Humanos , Inflamassomos/imunologia , Inflamação , Interleucina-1beta/imunologia , Lipopolissacarídeos/administração & dosagem , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/imunologia , Proteólise , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ubiquitina/genética , Ubiquitina/imunologia , Ubiquitinação
9.
Viruses ; 13(4)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808506

RESUMO

The rapid and dynamic activation of the innate immune system is achieved through complex signaling networks regulated by post-translational modifications modulating the subcellular localization, activity, and abundance of signaling molecules. Many constitutively expressed signaling molecules are present in the cell in inactive forms, and become functionally activated once they are modified with ubiquitin, and, in turn, inactivated by removal of the same post-translational mark. Moreover, upon infection resolution a rapid remodeling of the proteome needs to occur, ensuring the removal of induced response proteins to prevent hyperactivation. This review discusses the current knowledge on the negative regulation of innate immune signaling pathways by deubiquitinating enzymes, and through degradative ubiquitination. It focusses on spatiotemporal regulation of deubiquitinase and E3 ligase activities, mechanisms for re-establishing proteostasis, and degradation through immune-specific feedback mechanisms vs. general protein quality control pathways.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinação/fisiologia , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , Ligação Proteica , Processamento de Proteína Pós-Traducional , Transporte Proteico , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Ubiquitinação/genética , Ubiquitinação/imunologia
10.
Fish Shellfish Immunol ; 113: 118-124, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33848637

RESUMO

During viral infection, proper regulation of immune signaling is essential to ensure successful clearance of virus. Immunoproteasome is constitutively expressed and gets induced during viral infection by interferon signaling and contributes to regulate proinflammatory cytokine production and activation of the NF-κB pathway. In this study, we identified Hs-PSMB8, a member of the proteasome ß-subunits (PSMB) family, as a negative regulator of NF-κB responses during NNV infection. The transient expression of Hs-PSMB8 delayed the appearance of cytopathic effect (CPE) and showed a higher viral load. The Hs-PSMB8 interacted with NNV which was confirmed using immunocolocalization and co-IP. Overexpression of Hs-PSMB8 diminished virus induced activation of the NF-κB promoters and downregulated the activation of IL-1ß, TNFα, IL6, IL8, IFNγ expression upon NNV infection. Collectively, our results demonstrate that PSMB8 is an important regulator of NF-κB signaling during NNV infection in sevenband grouper.


Assuntos
Bass/genética , Bass/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , Sequência de Aminoácidos , Animais , Doenças dos Peixes/virologia , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , NF-kappa B/imunologia , Nodaviridae/fisiologia , Filogenia , Complexo de Endopeptidases do Proteassoma/química , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/veterinária , Infecções por Vírus de RNA/virologia , Alinhamento de Sequência/veterinária , Transdução de Sinais/imunologia
11.
Nat Commun ; 12(1): 739, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531497

RESUMO

The proteasome activator PA28αß affects MHC class I antigen presentation by associating with immunoproteasome core particles (iCPs). However, due to the lack of a mammalian PA28αß-iCP structure, how PA28αß regulates proteasome remains elusive. Here we present the complete architectures of the mammalian PA28αß-iCP immunoproteasome and free iCP at near atomic-resolution by cryo-EM, and determine the spatial arrangement between PA28αß and iCP through XL-MS. Our structures reveal a slight leaning of PA28αß towards the α3-α4 side of iCP, disturbing the allosteric network of the gatekeeper α2/3/4 subunits, resulting in a partial open iCP gate. We find that the binding and activation mechanism of iCP by PA28αß is distinct from those of constitutive CP by the homoheptameric TbPA26 or PfPA28. Our study sheds lights on the mechanism of enzymatic activity stimulation of immunoproteasome and suggests that PA28αß-iCP has experienced profound remodeling during evolution to achieve its current level of function in immune response.


Assuntos
Microscopia Crioeletrônica/métodos , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/ultraestrutura , Apresentação do Antígeno/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo
12.
Eur J Immunol ; 51(1): 138-150, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32686110

RESUMO

The IFN stimulated gene 15 (ISG15) encodes a 15-kDa ubiquitin-like protein, that is induced by type I IFNs and is conjugated to the bulk of newly synthesized polypeptides at the ribosome. ISG15 functions as an antiviral molecule possibly by being covalently conjugated to viral proteins and disturbing virus particle assembly. Here, we have investigated the effect of ISGylation on degradation and antigen presentation of viral and cellular proteins. ISGylation did not induce proteasomal degradation of bulk ISG15 target proteins neither after overexpressing ISG15 nor after induction by IFN-ß. The MHC class I cell surface expression of splenocytes derived from ISG15-deficient mice or mice lacking the catalytic activity of the major de-ISGylating enzyme USP18 was unaltered as compared to WT mice. Fusion of ubiquitin or FAT10 to the long-lived nucleoprotein (NP) of lymphocytic choriomeningitis virus accelerated the proteasomal degradation of NP while fusion to ISG15 did not detectably speed up NP degradation. Nevertheless, MHC-I restricted presentation of two epitopes of NP were markedly enhanced when it was fused to ISG15 similarly to fusion with ubiquitin or FAT10. Thus, we provide evidence that ISG15 can enhance the presentation of antigens on MHC-I most likely by promoting co-translational antigen processing.


Assuntos
Apresentação do Antígeno/imunologia , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Ubiquitinas/imunologia , Animais , Citocinas/deficiência , Citocinas/genética , Citocinas/metabolismo , Células HEK293 , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/imunologia , Proteínas do Nucleocapsídeo/metabolismo , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Modificação Traducional de Proteínas/imunologia , Proteólise , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologia , Ubiquitinas/deficiência , Ubiquitinas/genética , Ubiquitinas/metabolismo
13.
mBio ; 11(5)2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109760

RESUMO

The proteasome is a major protein degradation machinery with essential and diverse biological functions. Upon induction by cytokines, proteasome subunits ß1, ß2, and ß5 are replaced by ß1i/LMP2, ß2i/MECL-1, and ß5i/LMP7, resulting in the formation of an immunoproteasome (iProteasome). iProteasome-degraded products are loaded onto the major histocompatibility complex class I (MHC-I), regulating immune responses and inducing cytotoxic T lymphocytes (CTLs). Human immunodeficiency virus type 1 (HIV-1) is the causal agent of AIDS. HIV-1-specific CTLs represent a critical immune mechanism limiting viral replication. HIV-1 negative regulatory factor (Nef) counteracts host immunity, particularly the response involving MHC-I/CTL. This study identifies a distinct mechanism by which Nef facilitates immune evasion via suppressing the function of iProteasome and MHC-I. Nef interacts with LMP7 on the endoplasmic reticulum (ER), downregulating the incorporation of LMP7 into iProteasome and thereby attenuating its formation. Moreover, Nef represses the iProteasome function of protein degradation, MHC-I trafficking, and antigen presentation.IMPORTANCE The ubiquitin-proteasome system (UPS) is essential for the degradation of damaged proteins, which takes place in the proteasome. Upon activation by cytokines, the catalytic subunits of the proteasome are replaced by distinct isoforms resulting in the formation of an immunoproteasome (iProteasome). iProteasome generates peptides used by major histocompatibility complex class I (MHC-I) for antigen presentation and is essential for immune responses. HIV-1 is the causative agent of AIDS, and HIV-1-specific cytotoxic T lymphocytes (CTLs) provide immune responses limiting viral replication. This study identifies a distinct mechanism by which HIV-1 promotes immune evasion. The viral protein negative regulatory factor (Nef) interacts with a component of iProteasome, LMP7, attenuating iProteasome formation and protein degradation function, and thus repressing the MHC-I antigen presentation activity of MHC-I. Therefore, HIV-1 targets LMP7 to inhibit iProteasome activation, and LMP7 may be used as the target for the development of anti-HIV-1/AIDS therapy.


Assuntos
Apresentação do Antígeno , Antígenos de Histocompatibilidade Classe I/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Células HEK293 , Células HeLa , Humanos , Evasão da Resposta Imune
14.
Biochem Biophys Res Commun ; 533(4): 1012-1020, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33019975

RESUMO

Macrophages contribute to abdominal aortic aneurysm (AAA), but the effect of macrophage on AAA formation is not totally understood. Recent research proved that macrophage pyroptosis plays an important role in many cardiovascular disease. However, whether macrophage pyroptosis is involved in AAA and its mechanism remains unknown. In this study, we found that the pyroptosis significantly increased in AAA tissues. ß5i inhibitor PR-957 treatment or ß5i deficiency markedly ameliorated AAA formation and decreased the pyroptosis. Pyroptosis were also significantly attenuated in bone marrow derived macrophages (BMDM) from ß5i-/- mice compared with the control group when they were subjected to OXLDL. Mechanistically, ß5i may promote activation of NFκB which augment NLRP3 expression. In conclusion, this study suggested macrophages pyroptosis are involved in AAA and inhibition or knockout of ß5i decreased macrophage pyroptosis via IκB/NFκB pathway.


Assuntos
Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Macrófagos/imunologia , Macrófagos/patologia , Complexo de Endopeptidases do Proteassoma/imunologia , Piroptose/imunologia , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Piroptose/efeitos dos fármacos , Piroptose/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
J Immunol ; 205(8): 2255-2264, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32929041

RESUMO

The cytosolic pattern recognition receptor NLRP3 senses host-derived danger signals and certain microbe-derived products in both humans and rodents. NLRP3 activation assembles an inflammasome complex that contains the adapter proteins ASC and caspase-1, whose activation triggers the maturation and release of the proinflammatory cytokines IL-1ß and IL-18. S5 phosphorylation of NLRP3 prevents its oligomerization and activation, whereas dephosphorylation of this residue by the phosphatase PP2A allows NLRP3 activation. However, the protein kinase that mediates NLRP3 S5 phosphorylation is unknown. In this study, we show that AKT associates with NLRP3 and phosphorylates it on S5, limiting NLRP3 oligomerization. This phosphorylation event also stabilizes NLRP3 by reducing its ubiquitination on lysine 496, which inhibits its proteasome-mediated degradation by the E3 ligase Trim31. Pharmacologic manipulation of AKT kinase activity reciprocally modulates NLRP3 inflammasome-mediated IL-1ß production. Inhibition of AKT reduced IL-1ß production following the i.p. injection of LPS into mice. We propose that AKT, Trim31, and PP2A together modulate NLRP3 protein levels and the tendency to oligomerize, thereby setting a tightly regulated threshold for NLRP3 activation.


Assuntos
Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Animais , Caspase 1/imunologia , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Camundongos , Fosforilação/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Proteólise , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Ubiquitinação/imunologia
16.
Scand J Immunol ; 92(5): e12978, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32969499

RESUMO

MHC class I molecules on the cellular surface display peptides that either derive from endogenous proteins (self or viral), or from endocytosis of molecules, dying cells or pathogens. The conventional antigen-processing pathway for MHC class I presentation depends on proteasome-mediated degradation of the protein followed by transporter associated with antigen-processing (TAP)-mediated transport of the generated peptides into the endoplasmic reticulum (ER). Here, peptides are loaded onto MHC I molecules before transportation to the cell surface. However, several alternative mechanisms have emerged. These include TAP-independent mechanisms, the vacuolar pathway and involvement of autophagy. Autophagy is a cell intrinsic recycling system. It also functions as a defence mechanism that removes pathogens and damaged endocytic compartments from the cytosol. Therefore, it appears likely that autophagy would intersect with the MHC class I presentation pathway to alarm CD8+ T cells of an ongoing intracellular infection. However, the importance of autophagy as a source of antigen for presentation on MHC I molecules remains to be defined. Here, original research papers which suggest involvement of autophagy in MHC I antigen presentation are reviewed. The antigens are from herpesvirus, cytomegalovirus and chlamydia. The studies point towards autophagy as important in MHC class I presentation of endogenous proteins during conditions of immune evasion. Because autophagy is a regulated process which is induced upon activation of, for example, pattern recognition receptors (PRRs), it will be crucial to use relevant stimulatory conditions together with primary cells when aiming to confirm the importance of autophagy in MHC class I antigen presentation in future studies.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos/imunologia , Autofagia/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Animais , Antígenos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Transporte Proteico/imunologia
17.
Neurosci Lett ; 738: 135360, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32905834

RESUMO

The study was to investigate whether immunoproteasome (i-proteasome) and its downstream pathway are related to the pathogenesis of Parkinson's disease (PD). Rats were treated with rotenone showed significant weight loss and dyskinesia, which is consistent with the degeneration of TH-positive neurons and the activation of Iba-1-positive microglia/macrophages. Two major catalytic subunits of i-proteasome (PSMB9 and PSMB8) were seldom expressed in rat substantia nigra (SN) under normal condition, but they were significantly up-regulated with the release of TNF-α and IFN-γ after exposure to rotenone. In addition, compared with control group, the antigen presentation-related proteins antigen peptide transporter (TAP) 1, TAP2, major histocompatibility complex (MHC)-I and MHC-II levels were significantly up-regulated in rotenone group, which was in line with the accumulation of α-syn. These findings suggested that i-proteasome and antigen presentation pathways (related proteins) were upregulated by rotenone in a PD rat model.


Assuntos
Microglia/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Rotenona/farmacologia , Substância Negra/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Masculino , Microglia/metabolismo , Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos Wistar , Substância Negra/metabolismo , Regulação para Cima/efeitos dos fármacos , alfa-Sinucleína/metabolismo
18.
Int J Biol Sci ; 16(14): 2518-2526, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32792854

RESUMO

IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.


Assuntos
Glomerulonefrite por IGA/etiologia , Complexo de Endopeptidases do Proteassoma/imunologia , Apresentação do Antígeno , Linfócitos B/fisiologia , Citocinas/metabolismo , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/terapia , Humanos , Terapia de Alvo Molecular , Linfócitos T/fisiologia
19.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796072

RESUMO

Guanylate binding protein 5 (GBP5) belongs to the GTPase subfamily, which is mainly induced by interferon gamma (IFN-γ) and is involved in many important cellular processes, including inflammasome activation and innate immunity against a wide variety of microbial pathogens. However, it is unknown whether GBP5 inhibits respiratory syncytial virus (RSV) infection. In this study, we identified GBP5 as an effector of the anti-RSV activity of IFN-γ and found that in children, the weaker immune response, especially the weaker IFN-γ response and the decreased GBP5 expression, leads to RSV susceptibility. Furthermore, we revealed that GBP5 reduced the cell-associated levels of the RSV small hydrophobic (SH) protein, which was identified as a viroporin. In contrast, overexpression of the SH protein rescued RSV replication in the presence of GBP5. The GBP5-induced decrease in intracellular SH protein levels is because GBP5 promotes the release of the SH protein into the cell culture. Moreover, the GBP5 C583A mutants with changes at the C terminus or the GBP5 ΔC mutant lacking the C-terminal region, which impairs GBP5 localization in the Golgi, could not inhibit RSV infection, whereas the GTPase-defective GBP5 maintained RSV inhibition, suggesting that Golgi localization but not the GTPase activity of GBP5 is required for RSV inhibition. Interestingly, we found that RSV infection or RSV G protein downregulates GBP5 expression by upregulating DZIP3, an E3 ligase, which induces GBP5 degradation through the K48 ubiquitination and proteasomal pathways. Thus, this study reveals a complicated interplay between host restrictive factor GBP5 and RSV infection and provides important information for understanding the pathogenesis of RSV.IMPORTANCE RSV is a highly contagious virus that causes multiple infections in infants within their first year of life. It can also easily cause infection in elderly or immunocompromised individuals, suggesting that individual differences in immunity play an important role in RSV infection. Therefore, exploring the pathogenic mechanisms of RSV and identifying essential genes which inhibit RSV infection are necessary to develop an effective strategy to control RSV infection. Here, we report that the IFN-inducible gene GBP5 potently inhibits RSV replication by reducing the cell-associated levels of the RSV small hydrophobic (SH) protein, which is a viroporin. In contrast, the RSV G protein was shown to upregulate the expression of the DZIP3 protein, an E3 ligase that degrades GBP5 through the proteasomal pathway. Our study provides important information for the understanding of the pathogenic mechanisms of RSV and host immunity as well as the complicated interplay between the virus and host.


Assuntos
Proteínas de Ligação ao GTP/genética , Interações Hospedeiro-Patógeno/genética , Interferon gama/genética , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano/genética , Proteínas Oncogênicas de Retroviridae/genética , Adulto , Criança , Células Epiteliais/imunologia , Células Epiteliais/virologia , Feminino , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Complexo de Golgi/imunologia , Complexo de Golgi/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Inflamassomos/genética , Inflamassomos/imunologia , Interferon gama/imunologia , Masculino , Mutação , Complexo de Endopeptidases do Proteassoma/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
20.
Cell Death Dis ; 11(6): 419, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499535

RESUMO

Allogeneic mesenchymal stem cells (MSCs) are immunoprivileged and are being investigated in phase I and phase II clinical trials to treat different degenerative and autoimmune diseases. In spite of encouraging outcome of initial trials, the long-term poor survival of transplanted cells in the host tissue has declined the overall enthusiasm. Recent analyses of allogeneic MSCs based studies confirm that after transplantation in the hypoxic or ischemic microenvironment of diseased tissues, MSCs become immunogenic and are rejected by recipient immune system. The immunoprivilege of MSCs is preserved by absence or negligible expression of cell surface antigen, human leukocyte antigen (HLA)-DRα. We found that in normoxic MSCs, 26S proteasome degrades HLA-DRα and maintains immunoprivilege of MSCs. The exposure to hypoxia leads to inactivation of 26S proteasome and formation of immunoproteasome in MSCs, which is associated with upregulation and activation of HLA-DRα, and as a result, MSCs become immunogenic. Furthermore, inhibition of immunoproteasome formation in hypoxic MSCs preserves the immunoprivilege. Therefore, hypoxia-induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of allogeneic MSCs. The outcome of the current study may provide molecular targets to plan interventions to preserve immunoprivilege of allogeneic MSCs in the hypoxic or ischemic environment.


Assuntos
Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Complexo de Endopeptidases do Proteassoma/imunologia , Hipóxia Celular/imunologia , Regulação para Baixo , Cadeias alfa de HLA-DR/metabolismo , Humanos , Fenótipo , Subunidades Proteicas/metabolismo , Proteólise , Regulação para Cima
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