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1.
Yi Chuan ; 41(10): 893-904, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31624052

RESUMO

Mitochondrion is the metabolic center and powerhouse of cells producing cellular energy which plays an important role in various physiological and pathophysiological processes. Recent research demonstrates that mitochondrial energy metabolism mediates the transmission of mitochondrial-nuclear signals through intermediate products which regulates epigenetic presentation of the chromatin and thereby affects gene expression. Epigenetic modification, a genetic regulatory model, is independent of DNA sequence and plays a major role in establishing and maintaining a specific gene's expression profile. Disorders of mitochondrial metabolism can induce epigenetic reprogramming which in turn initiates aging phenotypes and degenerative diseases. This review introduces recent research progress on the relationship between mitochondrial metabolism and chromatin-related epigenetic modification, discusses the role of mitochondrial stress in chromatin recombination, and suggests future research directions and their application in the study of age-related diseases such as cognitive dysfunction.


Assuntos
Envelhecimento , Cromatina , Epigênese Genética , Mitocôndrias/metabolismo , Humanos
2.
J Immunol ; 203(6): 1560-1570, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31391232

RESUMO

STING plays central roles in the innate immune response to pathogens that contain DNA. Sensing cytoplasmic DNA by cyclic GMP-AMP synthase produces cyclic GMP-AMP, which binds to and activates STING and induces STING translocation from the endoplasmic reticulum to the perinuclear microsome. However, this trafficking process has not been fully elucidated yet. In this study, we identified YIPF5 as a positive regulator of STING trafficking. YIPF5 is essential for DNA virus- or intracellular DNA-triggered production of type I IFNs. Consistently, knockdown of YIPF5 impairs cellular antiviral responses to DNA virus. Mechanistically, YIPF5 interacts with both STING and components of COPII, facilitating STING recruitment to COPII in the presence of cytoplasmic dsDNA. Furthermore, knockdown of components of COPII inhibits DNA virus-triggered production of type I IFNs, suggesting that COPII is involved in innate immune responses to DNA viruses. Collectively, our findings demonstrate that YIPF5 positively regulates STING-mediated innate immune responses by recruiting STING to COPII-coated vesicles and facilitating STING trafficking from the endoplasmic reticulum to Golgi, providing important insights into the molecular mechanisms of intracellular DNA-stimulated STING trafficking and activation.

3.
BMC Complement Altern Med ; 19(1): 192, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362730

RESUMO

BACKGROUND: Acute postoperative pain remains a major clinical problem that affects patient recovery. Distal acupoint and peri-incisional stimulation are both used for relieving acute postoperative pain in hospital. Our objective was to assess and compare the effects of distal and peri-incisional stimulation on postoperative pain in open abdominal surgery. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Chinese databases CNKI and Wanfangdata were searched to identify eligible randomized controlled trials. Intensity of postoperative pain, opioid consumption and related data were extracted and analyzed using a random effects model. Risk of bias was assessed. Subgroup analyses were conducted when data were enough. RESULTS: Thirty-five trials were included, in which 17 trials studied distal stimulation, another 17 trials studied peri-incisional stimulation and one studied the combination of the two approaches. No studies that directly compared the two approaches were identified. Subgroup analysis showed that both distal and peri-incisional stimulation significantly alleviated postoperative resting and movement pain from 4 h to 48 h after surgery by 6 to 25 mm on a 100 mm visual analogue scale. Peri-incisional stimulation showed a better reduction in postoperative opioid consumption. No studies compared the effects of the combined peri-incisional and distal stimulation with either mode alone. Overall the quality of evidence was moderate due to a lack of blinding in some studies, and unclear risk of allocation concealment. CONCLUSION: Both distal and peri-incisional modes of stimulation were effective in reducing postoperative pain. Whether a combined peri-incisional stimulation and distal acupuncture has superior results requires further studies.

4.
Proc Natl Acad Sci U S A ; 116(21): 10447-10452, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31061131

RESUMO

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.

5.
PLoS Pathog ; 15(5): e1007691, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107917

RESUMO

Cyclic GMP-AMP synthase (cGAS) senses viral DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the ER-localized adaptor protein Mediator of IRF3 Activator (MITA) to initiate innate antiviral response. Human cytomegalovirus (HCMV) proteins can antagonize host immune responses to promote latent infection. Here, we identified HCMV UL42 as a negative regulator of cGAS/MITA-dependent antiviral response. UL42-deficiency enhances HCMV-induced production of type I interferons (IFNs) and downstream antiviral genes. Consistently, wild-type HCMV replicates more efficiently than UL42-deficient HCMV. UL42 interacts with both cGAS and MITA. UL42 inhibits DNA binding, oligomerization and enzymatic activity of cGAS. UL42 also impairs translocation of MITA from the ER to perinuclear punctate structures, which is required for MITA activation, by facilitating p62/LC3B-mediated degradation of translocon-associated protein ß (TRAPß). These results suggest that UL42 can antagonize innate immune response to HCMV by targeting the core components of viral DNA-triggered signaling pathways.


Assuntos
Antivirais/farmacologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Imunidade Inata/imunologia , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas Virais/farmacologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , DNA Viral/genética , DNA Viral/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/genética , Nucleotidiltransferases/genética , Transdução de Sinais
6.
J Virol ; 93(11)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867312

RESUMO

Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)- and NF-κB-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-κB to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level.IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-κB to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.

7.
Nat Chem Biol ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510190

RESUMO

Bacterial biofilms can be programmed to produce living materials with self-healing and evolvable functionalities. However, the wider use of artificial biofilms has been hindered by limitations on processability and functional protein secretion capacity. We describe a highly flexible and tunable living functional materials platform based on the TasA amyloid machinery of the bacterium Bacillus subtilis. We demonstrate that genetically programmable TasA fusion proteins harboring diverse functional proteins or domains can be secreted and can assemble into diverse extracellular nano-architectures with tunable physicochemical properties. Our engineered biofilms have the viscoelastic behaviors of hydrogels and can be precisely fabricated into microstructures having a diversity of three-dimensional (3D) shapes using 3D printing and microencapsulation techniques. Notably, these long-lasting and environmentally responsive fabricated living materials remain alive, self-regenerative, and functional. This new tunable platform offers previously unattainable properties for a variety of living functional materials having potential applications in biomaterials, biotechnology, and biomedicine.

8.
Nat Commun ; 9(1): 3441, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143645

RESUMO

STAT3 is a transcription factor that plays central roles in various physiological processes and its deregulation results in serious diseases including cancer. The mechanisms on how STAT3 activity is regulated remains enigmatic. Here we identify TRIM27 as a positive regulator of II-6-induced STAT3 activation and downstream gene expression. TRIM27 localizes to retromer-positive punctate structures and serves as a critical link for recruiting gp130, JAK1, and STAT3 to and subsequent phosphorylation of STAT3 at the retromer-positive structures. Overexpression of TRIM27 promotes cancer cell growth in vitro and tumor growth in nude mice, whereas knockdown of TRIM27 has opposite effects. Deficiency of TRIM27 significantly impairs dextran sulfate sodium (DSS)-induced STAT3 activation, inflammatory cytokine expression and colitis as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. These findings reveal a retromer-dependent mechanism for regulation of STAT3 activation, inflammation, and inflammation-associated cancer development.

9.
J Innate Immun ; 10(4): 315-327, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30016790

RESUMO

As a key molecule in the antiviral innate immune response, the activation of TANK-binding kinase 1 (TBK1) is under tight regulation. In this report, we identified phosphatidylserine-specific phospholipase PLA1A as a host factor that modulates the TBK1 activation. Knockdown of PLA1A expression suppressed the innate immune signaling induced by RNA viruses, while PLA1A overexpression enhanced the signaling. PLA1A functioned at the TBK1 level of the signaling pathway, as PLA1A silencing blocked TBK1, but not interferon regulatory factor 3 (IRF3) induced interferon-ß (IFN-ß) promoter activity. The phosphorylation and kinase activity of TBK1 was reduced in PLA1A knockdown cells. Mechanistically, PLA1A was required in TBK1-mitochondrial antiviral signaling protein (MAVS) interactions but not the interactions of TBK1 with other adaptor proteins. Furthermore, PLA1A knockdown reduced the recruitment of TBK1 and IRF3 to mitochondria, concomitant with altered mitochondria morphology.

10.
Pain Med ; 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29893942

RESUMO

Objectives: To evaluate the efficacy and safety of electroacupuncture in reducing opioid consumption in patients with chronic musculoskeletal pain. Design: A randomized, participant-assessor-blinded, three-arm trial. Setting: Participants from three pain clinics and from the public. Subjects: One hundred and eight adults with chronic pain who were taking opioids. Methods: All participants received pain and medication management education. Participants were randomly allocated to electroacupuncture (N = 48), sham electroacupuncture (N = 29), or education alone (N = 31) to receive relevant treatment for 12 weeks. The last group received electroacupuncture during the three-month follow-up. Analysis of covariance and paired t tested were used. Results: Opioid dosage, that is, the primary outcome measure, was reduced by 20.5% (P < 0.05) and 13.7% (P < 0.01) in the two acupuncture groups and by 4.5% in the education group at the end of the treatment phase, but without any group difference. Intensity of pain of all three groups did not change over time. No group differences were found in dosage of nonopioid analgesics, pain intensity, function, and opioid-related adverse events. During follow-up, the education group had a 47% reduction of opioids after a course of electroacupuncture. Adverse events to electroacupuncture were minor. Conclusion: It is safe to reduce opioid medication use in patients with chronic pain. Due to the small sample size, we could not confirm if electroacupuncture offers extra benefit in addition to education. This nondrug therapy could be a promising adjunct to facilitate opioid tapering in patients who are willing to reduce opioids.

11.
Cell Host Microbe ; 24(1): 69-80.e4, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29937271

RESUMO

The cytosolic DNA sensor cGAS recognizes viral DNA and synthesizes the second messenger cGAMP upon viral infection. cGAMP binds to the adaptor protein MITA/STING to activate downstream signaling events, leading to induction of type I interferons (IFNs) and antiviral effector genes. Here we identify the human cytomegalovirus (HCMV) protein UL31 as an inhibitor of cGAS. UL31 interacts directly with cGAS and disassociates DNA from cGAS, thus inhibiting cGAS enzymatic functions and reducing cGAMP production. UL31 overexpression markedly reduces antiviral responses stimulated by cytosolic DNA, while knockdown or knockout of UL31 heightens HCMV-triggered induction of type I IFNs and downstream antiviral genes. Moreover, wild-type HCMV replicates more efficiently than UL31-deficient HCMV, a phenotype that is reversed in cGAS null cells. These results highlight the importance of cGAS in the host response to HCMV as well as an important viral strategy to evade this innate immune sensor.

12.
J Mol Cell Biol ; 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29800227

RESUMO

Class II HDACs, such as HDAC4, are critical regulators of the immune response in various immune cells; however, its role in innate immunity remains largely unknown. Here, we report that the overexpression of HDAC4 suppresses the production of type I interferons triggered by pattern-recognition receptors (PRRs). HDAC4 repressed the translocation of transcription factor IRF3 to the nucleus, thereby decreasing IRF3-mediated IFN-ß expression. In particular, we also determined that HDAC4 can be phosphorylated and simultaneously block the phosphorylation of IRF3 at Ser386 and Ser396 by TBK1 and IKKε, respectively, by interacting with the kinase domain of TBK1 and IKKε. Furthermore, IFN-ß may stimulate the expression of HDAC4. Our findings suggest that HDAC4 acts as a regulator of PRR signaling and is a novel mechanism of negative feedback regulation for preventing an over-reactive innate immune response.

13.
Acupunct Med ; 36(4): 204-214, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29669794

RESUMO

BACKGROUND: An ideal placebo design in clinical research should resemble the intervention under investigation to facilitate blinding, yet remain clinically inert. With regard to physical interventions such as acupuncture, a true placebo device has not been developed and validated. Since 1998, researchers have designed several placebo acupuncture devices (PADs). The three most widely used PADs are the Streitberger, the Park and the Takakura device. AIM: This review focuses on evaluating studies of these devices, in the context of credibility of blinding (COB), assessment of penetrating pain or sensation, and de qi sensation. METHODS: Electronic database searches were conducted in four English and two Chinese databases from their inception until November 2016. All studies included in the review were conducted on healthy participants and compared verum manual acupuncture with any of the aforementioned PADs with respect to one or more of the above three outcomes related to blinding effect. RESULTS: The synthesised analyses of the 15 included studies showed that the Streitberger and Park placebo devices may not blind participants successfully when tested at a sensitive acupuncture point (LI4). In terms of penetrating sensation, there were significant differences between these two placebo devices and verum acupuncture when applied at this point. The Takakura device was the only PAD that had the potential to blind the acupuncturist. However, the blinding analyses of all outcome measures were inconsistent. CONCLUSION: Overall, there were insufficient data to confirm the blinding effects of these skin-contact PADs as each device was associated with limitations that warrant further design improvements.

14.
J Mol Biol ; 430(20): 3720-3734, 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-29702108

RESUMO

Many living organisms make use of diverse amyloid proteins as functional building blocks to fulfill a variety of physiological applications. This fact, along with the intrinsic self-assembly and outstanding material properties of amyloids, has prompted a significant amount of research in the synthetic design of functional amyloids to form diverse nanoarchitectures, molecular materials, and hybrid or composite materials. In particular, a new research paradigm has recently been advanced that uses synthetic biology to harness functional amyloids with cells as living materials or functional devices. Here we outline important progress in the synthetic design of functional amyloids, in the context of both non-living and living systems. We propose several important tools and underline emerging techniques and principles that might be useful in advancing the future synthetic design of functional amyloids.

15.
Virol Sin ; 33(2): 117-124, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29546673

RESUMO

The cGAS-MITA pathway of cytosolic DNA sensing plays essential roles in immune response against pathogens that contain DNA or with DNA production in their life cycles. The cGAS-MITA pathway also detects leaked or aberrant accumulated self DNA in the cytoplasm under certain pathological conditions, such as virus induced cell death, DNA damage, mitochondria damage, gene mutations, which results in autoimmune diseases. Therefore, the cGAS-MITA pathway must be tightly controlled to ensure proper immune response against pathogens and to avoid autoimmune diseases. The regulation of cGAS-MITA pathway at MITA-level have been extensively explored and reviewed elsewhere, here we provide a summary and perspective on recent advances in understanding of the cGAS regulation.


Assuntos
DNA/imunologia , DNA/metabolismo , Regulação da Expressão Gênica , Imunidade Inata , Proteínas de Membrana/metabolismo , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/metabolismo , Animais , Humanos , Redes e Vias Metabólicas
16.
Gene Ther ; 25(3): 220-233, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29523881

RESUMO

Current in vivo selections for hematopoietic stem cell (HSC)-based gene therapy are drug dependent and not without risk of cytotoxicity or tumorigenesis. We developed a new in vivo selection system with the non-phosphorylatable Bcl2 mutant Bcl2T69A/S70A/S87A (Bcl2AAA), which makes in vivo selection drug independent and without risk of cytotoxicity or tumorigenesis. We demonstrated in HSC-transplanted mice that Bcl2AAA facilitated efficient in vivo selection in the absence of any exogenously applied drugs under both myeloablative and non-myeloablative conditioning. In mice transplanted with retrovirally transduced sca-1-positive bone marrow cells, the marked cell level increased from 26.38% of input transduced cells to 92.61 ± 0.95% of peripheral blood cells for myeloablative transplantation or to 37.82 ± 6.35% for non-myeloablative transplantation 6 months after transplantation. Bcl2AAA did not induce tumorigenesis and does not influence hematopoiesis and the function of the reconstituted blood system. However, the high-level constitutive expression of Bcl2AAA mediated by retroviral vector induced exhaustion of the marked cells after tertiary transplantation. Fortunately, low-level constitutive expression of Bcl2AAA driven by an internal promoter in lentiviral vector could both maintain the marked cell level (24.13 ± 5.27%, 27.17 ± 5.51%, 24.33 ± 5.08%, and 22.07 ± 4.44% for primary, secondary, tertiary, and quaternary recipients) and avoid the exhaustion of the marked cells even in quaternary recipients. Importantly, the low-level constitutive expression of Bcl2AAA did not induce tumorigenesis. Thus, the in vivo selection employing the low-level constitutive expression of Bcl2AAA provides a general platform which is relevant for widespread applications of gene therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Células da Medula Óssea , Terapia Genética , Vetores Genéticos , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
17.
J Pain ; 19(8): 897-909, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29597084

RESUMO

Healthy humans can be divided into the pain adaptive (PA) and the pain nonadaptive (PNA) groups; PA showed a greater decrease in pain rating to a cold pressor test (CPT) than PNA. This study examined if the dichotomy of pain adaptability existed in individuals with chronic musculoskeletal pain. CPTs at 2°C and 7°C were used to assess the status of pain adaptability in participants with either chronic nonspecific low back pain or knee osteoarthritis. The participants' potency of conditioned pain modulation (CPM) and local inhibition were measured. The strengths of pain adaptability at both CPTs were highly correlated. PA and PNA did not differ in their demographic characteristics, pain thresholds from thermal and pressure stimuli, or potency of local inhibition or CPM. PA reached their maximum pain faster than PNA (t41 = -2.76, P < .01), and had a gradual reduction of pain unpleasantness over 7 days whereas PNA did not (F6,246 = 3.01, P = .01). The dichotomy of pain adaptability exists in musculoskeletal pain patients. Consistent with the healthy human study, the strength of pain adaptability and potency of CPM are not related. Pain adaptability could be another form of endogenous pain inhibition of which clinical implication is yet to be understood. PERSPECTIVE: The dichotomy of pain adaptability was identified in healthy humans. The current study confirms that this dichotomy also exists in individuals with chronic musculoskeletal pain, and could be reliably assessed with CPTs at 2°C and 7°C. Similar to the healthy human study, pain adaptability is not associated with CPM, and may reflect the temporal aspect of pain inhibition.

18.
J Virol ; 92(9)2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29437978

RESUMO

WD repeat-containing protein 5 (WDR5) is essential for assembling the VISA-associated complex to induce a type I interferon antiviral response to Sendai virus infection. However, the roles of WDR5 in DNA virus infections are not well described. Here, we report that human cytomegalovirus exploits WDR5 to facilitate capsid nuclear egress. Overexpression of WDR5 in fibroblasts slightly enhanced the infectious virus yield. However, WDR5 knockdown dramatically reduced infectious virus titers with only a small decrease in viral genome replication or gene expression. Further investigation of late steps of viral replication found that WDR5 knockdown significantly impaired formation of the viral nuclear egress complex and induced substantially fewer infoldings of the inner nuclear membrane. In addition, fewer capsids were associated with these infoldings, and there were fewer capsids in the cytoplasm. Restoration of WDR5 partially reversed these effects. These results suggest that WDR5 knockdown impairs the nuclear egress of capsids, which in turn decreases virus titers. These findings reveal an important role for a host factor whose function(s) is usurped by a viral pathogen to promote efficient replication. Thus, WDR5 represents an interesting regulatory mechanism and a potential antiviral target.IMPORTANCE Human cytomegalovirus (HCMV) has a large (∼235-kb) genome with over 170 open reading frames and exploits numerous cellular factors to facilitate its replication. HCMV infection increases protein levels of WD repeat-containing protein 5 (WDR5) during infection, overexpression of WDR5 enhances viral replication, and knockdown of WDR5 dramatically attenuates viral replication. Our results indicate that WDR5 promotes the nuclear egress of viral capsids, the depletion of WDR5 resulting in a significant decrease in production of infectious virions. This is the first report that WDR5 favors HCMV, a DNA virus, replication and highlights a novel target for antiviral therapy.


Assuntos
Capsídeo/metabolismo , Citomegalovirus/fisiologia , Replicação do DNA/genética , DNA Viral/biossíntese , Histona-Lisina N-Metiltransferase/metabolismo , Replicação Viral/fisiologia , Linhagem Celular , Sobrevivência Celular , DNA Viral/genética , Genoma Viral/genética , Células HEK293 , Histona-Lisina N-Metiltransferase/genética , Humanos , Pulmão/citologia , Pulmão/virologia , Transporte Proteico/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Regulação para Cima , Carga Viral/genética , Internalização do Vírus
19.
PLoS Pathog ; 13(11): e1006693, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29155878

RESUMO

VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/imunologia , Degradação Associada com o Retículo Endoplasmático , Imunidade Inata , Infecções por Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteólise , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/metabolismo , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
20.
Cranio ; : 1-7, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28937319

RESUMO

OBJECTIVE: To observe the characteristics of brain activation during unilateral premolar occlusion. METHODS: Functional magnetic resonance imaging was collected from 10 healthy volunteers during occlusion of the left first premolar (L1), left second premolar (L2), and right first premolar (R1). The brain activation patterns were analyzed, and the primary sensorimotor cortex, supplementary motor area, insula, thalamus, and prefrontal cortex were chosen as regions of interest. RESULTS: Single premolar occlusion activated the precentral gyrus, postcentral gyrus, cerebellum, thalamus, frontal lobe, hippocampus, cingulate gyrus, and parietal lobe. The brain areas showing activation during single premolar occlusion were similar to those activated by chewing. The activation pattern of L1 was more similar to that of L2 than R1. No significant left and right hemisphere differences in signal intensity were detected within the regions of interest. CONCLUSION: Brain activation patterns from two ipsilateral premolars were more similar than the pattern from a contralateral premolar.

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