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1.
Int Immunopharmacol ; 133: 112123, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38663314

RESUMO

The NOD-like receptor family protein 3 (NLRP3) inflammasome is a crucial complex for the host to establish inflammatory immune responses and plays vital roles in a series of disorders, including Alzheimer's disease and acute peritonitis. However, its regulatory mechanism remains largely unclear. Zinc finger antiviral protein (ZAP), also known as zinc finger CCCH-type antiviral protein 1 (ZC3HAV1), promotes viral RNA degradation and plays vital roles in host antiviral immune responses. However, the role of ZAP in inflammation, especially in NLRP3 activation, is unclear. Here, we show that ZAP interacts with NLRP3 and promotes NLRP3 oligomerization, thus facilitating NLRP3 inflammasome activation in peritoneal macrophages of C57BL/6 mice. The shorter isoform of ZAP (ZAPS) appears to play a greater role than the full-length isoform (ZAPL) in HEK293T cells. Congruously, Zap-deficient C57BL/6 mice may be less susceptible to alum-induced peritonitis and lipopolysaccharide-induced sepsis in vivo. Therefore, we propose that ZAP is a positive regulator of NLRP3 activation and a potential therapeutic target for NLRP3-related inflammatory disorders.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Peritonite , Animais , Humanos , Masculino , Camundongos , Células HEK293 , Inflamassomos/metabolismo , Inflamassomos/imunologia , Lipopolissacarídeos/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Peritonite/imunologia , Peritonite/induzido quimicamente , Multimerização Proteica , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Sepse/imunologia , Sepse/metabolismo
2.
Nat Commun ; 15(1): 1750, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409248

RESUMO

Oxidative (or respiratory) burst confers host defense against pathogens by generating reactive species, including reactive nitrogen species (RNS). The microbial infection-induced excessive RNS damages many biological molecules via S-nitrosothiol (SNO) accumulation. However, the mechanism by which the host enables innate immunity activation during oxidative burst remains largely unknown. Here, we demonstrate that S-nitrosoglutathione (GSNO), the main endogenous SNO, attenuates innate immune responses against herpes simplex virus-1 (HSV-1) and Listeria monocytogenes infections. Mechanistically, GSNO induces the S-nitrosylation of stimulator of interferon genes (STING) at Cys257, inhibiting its binding to the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Alcohol dehydrogenase 5 (ADH5), the key enzyme that metabolizes GSNO to decrease cellular SNOs, facilitates STING activation by inhibiting S-nitrosylation. Concordantly, Adh5 deficiency show defective STING-dependent immune responses upon microbial challenge and facilitates viral replication. Thus, cellular oxidative burst-induced RNS attenuates the STING-mediated innate immune responses to microbial infection, while ADH5 licenses STING activation by maintaining cellular SNO homeostasis.


Assuntos
Aldeído Oxirredutases , Herpesvirus Humano 1 , S-Nitrosotióis , Proteínas de Membrana/metabolismo , Imunidade Inata , Homeostase
3.
PLoS Pathog ; 19(4): e1011314, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37023217

RESUMO

Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo. Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.


Assuntos
Herpesvirus Humano 1 , Antivirais , Herpesvirus Humano 1/fisiologia , Imunidade Inata , Selenoproteínas , Replicação Viral/genética , Humanos , Animais , Camundongos
4.
Nat Commun ; 14(1): 660, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36750575

RESUMO

Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of STING-induced interferon (IFN) responses. Thus, the mechanisms that ensure the beneficial effects of STING activation are of particular importance. Herein, we show that myristic acid, a type of long-chain saturated fatty acid (SFA), specifically attenuates cGAS-STING-induced IFN responses in macrophages, while enhancing STING-dependent autophagy. Myristic acid inhibits HSV-1 infection-induced innate antiviral immune responses and promotes HSV-1 replication in mice in vivo. Mechanistically, myristic acid enhances N-myristoylation of ARF1, a master regulator that controls STING membrane trafficking. Consequently, myristic acid facilitates STING activation-triggered autophagy degradation of the STING complex. Thus, our work identifies myristic acid as a metabolic checkpoint that contributes to immune homeostasis by balancing STING-dependent autophagy and IFN responses. This suggests that myristic acid and N-myristoylation are promising targets for the treatment of diseases caused by aberrant STING activation.


Assuntos
Proteínas de Membrana , Transdução de Sinais , Animais , Camundongos , Autofagia , Imunidade Inata , Interferons , Proteínas de Membrana/metabolismo , Ácido Mirístico , Nucleotidiltransferases/metabolismo
5.
Nat Immunol ; 21(7): 727-735, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541831

RESUMO

Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS-STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress-induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.


Assuntos
Herpes Simples/imunologia , Proteínas de Membrana/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Carbolinas/farmacologia , Células Cultivadas , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Feminino , Fibroblastos , Complexo de Golgi/metabolismo , Células HEK293 , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Homeostase/imunologia , Humanos , Imunidade Inata , Peroxidação de Lipídeos/genética , Peroxidação de Lipídeos/imunologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Nucleotidiltransferases/metabolismo , Oxirredução , Oximas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Cultura Primária de Células , Carbonilação Proteica/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Células THP-1 , Replicação Viral/imunologia
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