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1.
Res Sq ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38883790

RESUMO

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is docked at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-ß responses. UBXN9 deletion prompts constitutive GLUT4 trafficking, sequestration of RLRs, and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

2.
Nat Commun ; 15(1): 780, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38278841

RESUMO

The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.


Assuntos
Vírus de RNA , Camundongos , Animais , Ubiquitinação , Linhagem Celular , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Imunidade Inata , Ubiquitina-Proteína Ligases/metabolismo , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo
3.
Biomed Pharmacother ; 170: 115993, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38091635

RESUMO

Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α2A-adrenoceptor deficient (Adra2a-/-) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a-/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a-/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α2A-adrenoceptor dependent manner.


Assuntos
Cardiomiopatias , Dexmedetomidina , Cardiopatias , Sepse , Humanos , Camundongos , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Sepse/tratamento farmacológico , Glucose/uso terapêutico , Ácidos Graxos
4.
mBio ; 13(6): e0268722, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36377866

RESUMO

Ubiquitin regulatory X domain-containing proteins (UBXN) might be involved in diverse cellular processes. However, their in vivo physiological functions remain largely elusive. We recently showed that UBXN3B positively regulated stimulator-of-interferon-genes (STING)-mediated innate immune responses to DNA viruses. Herein, we reported the essential role of UBXN3B in the control of infection and immunopathogenesis of two arthritogenic RNA viruses, Chikungunya (CHIKV) and O'nyong'nyong (ONNV) viruses. Ubxn3b deficient (Ubxn3b-/-) mice presented higher viral loads, more severe foot swelling and immune infiltrates, and slower clearance of viruses and resolution of inflammation than the Ubxn3b+/+ littermates. While the serum cytokine levels were intact, the virus-specific immunoglobulin G and neutralizing antibody levels were lower in the Ubxn3b-/- mice. The Ubxn3b-/- mice had more neutrophils and macrophages, but much fewer B cells in the ipsilateral feet. Of note, this immune dysregulation was also observed in the spleens and blood of uninfected Ubxn3b-/- mice. UBXN3B restricted CHIKV replication in a cell-intrinsic manner but independent of type I IFN signaling. These results demonstrated a dual role of UBXN3B in the maintenance of immune homeostasis and control of RNA virus replication. IMPORTANCE The human genome encodes 13 ubiquitin regulatory X (UBX) domain-containing proteins (UBXN) that might participate in diverse cellular processes. However, their in vivo physiological functions remain largely elusive. Herein, we reported an essential role of UBXN3B in the control of infection and immunopathogenesis of arthritogenic alphaviruses, including Chikungunya virus (CHIKV), which causes acute and chronic crippling arthralgia, long-term neurological disorders, and poses a significant public health problem in the tropical and subtropical regions worldwide. However, there are no approved vaccines or specific antiviral drugs. This was partly due to a poor understanding of the protective and detrimental immune responses elicited by CHIKV. We showed that UBXN3B was critical for the control of CHIKV replication in a cell-intrinsic manner in the acute phase and persistent immunopathogenesis in the post-viremic stage. Mechanistically, UBXN3B was essential for the maintenance of hematopoietic homeostasis during viral infection and in steady-state.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Vírus , Humanos , Animais , Camundongos , Vírus Chikungunya/genética , Febre de Chikungunya/patologia , Antivirais/farmacologia , Ubiquitinas , Replicação Viral
5.
Commun Biol ; 5(1): 96, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35079095

RESUMO

Intrinsic cardiac adrenergic (ICA) cells regulate both developing and adult cardiac physiological and pathological processes. However, the role of ICA cells in septic cardiomyopathy is unknown. Here we show that norepinephrine (NE) secretion from ICA cells is increased through activation of Toll-like receptor 4 (TLR4) to aggravate myocardial TNF-α production and dysfunction by lipopolysaccharide (LPS). In ICA cells, LPS activated TLR4-MyD88/TRIF-AP-1 signaling that promoted NE biosynthesis through expression of tyrosine hydroxylase, but did not trigger TNF-α production due to impairment of p65 translocation. In a co-culture consisting of LPS-treated ICA cells and cardiomyocytes, the upregulation and secretion of NE from ICA cells activated cardiomyocyte ß1-adrenergic receptor driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to crosstalk with NF-κB and mitogen-activated protein kinase pathways. Importantly, blockade of ICA cell-derived NE prevented LPS-induced myocardial dysfunction. Our findings suggest that ICA cells may be a potential therapeutic target for septic cardiomyopathy.


Assuntos
Cardiomiopatias/induzido quimicamente , Fármacos Cardiovasculares/farmacologia , Lipopolissacarídeos/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Norepinefrina/metabolismo , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like
6.
Infect Med (Beijing) ; 1(3): 208-216, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38077630

RESUMO

Innate immune signaling plays a significant role in the rapid cellular responses against foreign entities. An inflammasome is a large cytosolic polymer of a pattern recognition receptor with/without an adaptor protein, formed in response to these entities. Canonically, an inflammasome can recruit and lead to auto-activation of caspase-1, subsequent maturation and secretion of inflammatory cytokines, and pyroptosis. One particular inflammasome, the noncanonical inflammasome, is formed by caspase-4 or -5 (mouse caspase-11) upon binding of lipopolysaccharide and is essential for controlling gram-negative bacterial infection. However, prolonged hyper-activation of the non-canonical inflammasome has been implicated in the pathogenesis of inflammatory diseases and endotoxemia sepsis. This review will summarize the recent advances on the noncanonical inflammasome, its mechanism of activation, key cellular regulators and role in health and disease.

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