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1.
Nat Cell Biol ; 23(4): 330-340, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33833429

RESUMO

Biomolecular condensates (biocondensates) formed via liquid-liquid phase-separation of soluble proteins have been studied extensively. However, neither the phase-separation of endoplasmic reticulum (ER) transmembrane protein nor a biocondensate with organized membranous structures has been reported. Here, we have discovered a spherical ER membranous biocondensate with puzzle-like structures caused by condensation of the ER-resident stimulator of interferon genes (STING) in DNA virus-infected or 2'3'-cGAMP (cyclic GMP-AMP)-treated cells, which required STING transmembrane domains, an intrinsically disordered region (IDR) and a dimerization domain. Intracellular 2'3'-cGAMP concentrations determined STING translocation or condensation. STING biocondensates constrained STING and TBK1 (TANK binding protein 1) to prevent innate immunity from overactivation, presumably acting like a 'STING-TBK1-cGAMP sponge'. Cells expressing STING-E336G/E337G showed notably enhanced innate immune responses due to impaired STING condensation after viral infection at later stages. Microtubule inhibitors impeded the STING condensate gel-like transition and augmented type I-interferon production in DNA virus-infected cells. This membranous biocondensate was therefore named the STING phase-separator.


Assuntos
Retículo Endoplasmático/genética , Imunidade Inata/genética , Extração Líquido-Líquido , Proteínas de Membrana/genética , Humanos , Nucleotídeos Cíclicos/genética , Ligação Proteica/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética
2.
Cell Mol Immunol ; 18(5): 1222-1234, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33767434

RESUMO

Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2'3'-cGAMP. Herein, we found that Mn2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4+/CD8+ T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.


Assuntos
Adjuvantes Imunológicos/farmacologia , Manganês/farmacologia , Sais/farmacologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Antivirais/farmacologia , Vacinas Anticâncer/imunologia , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Interleucina-1/biossíntese , Interleucina-18/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nucleotidiltransferases/metabolismo , Subunidades Proteicas/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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