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1.
J Biol Chem ; 293(7): 2358-2369, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29301938

RESUMO

The nucleoli accumulate rRNA genes and are the sites of rRNA synthesis and rRNA assembly into ribosomes. During mitosis, nucleoli dissociate, but nucleolar remnants remain on the rRNA gene loci, forming distinct nucleolar organizer regions (NORs). Little is known about the composition and structure of NORs, but upstream binding factor (UBF) has been established as its master organizer. In this study, we sought to establish new proteins in NORs. Using UBF-Sepharose to isolate UBF-binding proteins, we identified histone H1.2 as a candidate partner but were puzzled by this observation, given that UBF is known to be located predominantly in nucleoli, whereas H1.2 distributed broadly among the chromatins in interphase nuclei. We then examined cells undergoing mitosis and saw that both H1.2 and UBF were recruited into NORs in this state, reconciling the results of our UBF pulldowns. Inhibiting rRNA synthesis in interphase nuclei also induced NOR-like structures containing both UBF and H1.2. When chromosomes were isolated and spread on coverslips, NORs appeared separated from the chromosomes containing both UBF and H1.2. After chromosomes were fragmented by homogenization, intact NORs remained visible. Results collectively suggest that NORs are independent structures and that the linker histone H1.2 is a novel component of this structure.


Assuntos
Histonas/metabolismo , Região Organizadora do Nucléolo/metabolismo , Cromatina/genética , Cromatina/metabolismo , Histonas/genética , Humanos , Mitose , Região Organizadora do Nucléolo/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Transcrição Gênica
2.
J Immunol ; 199(12): 3981-3990, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29070672

RESUMO

Anti-nuclear autoantibodies, which frequently target the nucleoli, are pathogenic hallmarks of systemic lupus erythematosus (SLE). Although the causes of these Abs remain broad and ill-defined, a genetic deficiency in C1 complex (C1qC1r2C1s2) or C4 is able to induce these Abs. Considering a recent finding that, in dead cells, nucleoli were targeted by C1q and two nucleolar autoantigens were degraded by C1r/C1s proteases, we considered that C1 could help protect against antinuclear autoimmunity by broadly degrading nucleolar proteins or autoantigens. Nucleoli were isolated to homogeneity and structurally defined. After C1 treatment, cleaved nucleolar proteins were identified by proteomic two-dimensional fluorescence difference gel electrophoresis and mass spectrometry, and further verified by Western blotting using specific Abs. The extent of nucleolar autoantigen degradation upon C1 treatment was estimated using SLE patient autoantibodies. The isolated nucleoli were broadly reactive with SLE patient autoantibodies. These nucleoli lacked significant autoproteolysis, but many nucleolar proteins and autoantigens were degraded by C1 proteases; >20 nucleolar proteins were identified as C1 cleavable. These were further validated by Western blotting using specific Abs. The broad autoantigenicity of the nucleoli may attribute to their poor autoproteolysis, causing autologous immune stimulation upon necrotic exposure. However, C1q targets at these nucleoli to cause C1 protease activation and the cleavage of many nucleolar proteins or autoantigens. This may represent one important surveillance mechanism against antinuclear autoimmunity because C1 genetic deficiency causes anti-nuclear autoantibodies and SLE disease.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/metabolismo , Nucléolo Celular/imunologia , Complemento C1r/metabolismo , Complemento C1s/metabolismo , Imunoglobulina G/imunologia , Proteínas Nucleares/metabolismo , Autoanticorpos/sangue , Nucléolo Celular/ultraestrutura , Células HeLa , Humanos , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Proteólise , Proteômica , Especificidade por Substrato
3.
J Biol Chem ; 290(37): 22570-80, 2015 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-26231209

RESUMO

In infection, complement C1q recognizes pathogen-congregated antibodies and elicits complement activation. Among endogenous ligands, C1q binds to DNA and apoptotic cells, but whether C1q binds to nuclear DNA in apoptotic cells remains to be investigated. With UV irradiation-induced apoptosis, C1q initially bound to peripheral cellular regions in early apoptotic cells. By 6 h, binding concentrated in the nuclei to the nucleolus but not the chromatins. When nucleoli were isolated from non-apoptotic cells, C1q also bound to these structures. In vivo, C1q exists as the C1 complex (C1qC1r2C1s2), and C1q binding to ligands activates the C1r/C1s proteases. Incubation of nucleoli with C1 caused degradation of the nucleolar proteins nucleolin and nucleophosmin 1. This was inhibited by the C1 inhibitor. The nucleoli are abundant with autoantigens. C1q binding and C1r/C1s degradation of nucleolar antigens during cell apoptosis potentially reduces autoimmunity. These findings help us to understand why genetic C1q and C1r/C1s deficiencies cause systemic lupus erythematosus.


Assuntos
Apoptose/efeitos da radiação , Nucléolo Celular/metabolismo , Complemento C1q/metabolismo , Complemento C1r/metabolismo , Complemento C1s/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteólise/efeitos da radiação , Proteínas de Ligação a RNA/metabolismo , Raios Ultravioleta , Células HeLa , Humanos , Nucleofosmina , Nucleolina
4.
Drug Alcohol Depend ; 181: 30-36, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031090

RESUMO

BACKGROUND: Recreational drug use has increased in recent years, especially among MSM, and has been found to be associated with higher risk of HIV infection. However, there is limited information about current recreational drug use among MSM in Shenzhen which is an international gateway city to China with a rapidly expanding MSM population. METHODS: A cross-sectional survey among MSM in Shenzhen was conducted and was used to collected information on demographics, sexual behavior and drug use via questionnaires. Serologic results on HIV and syphilis were obtained from laboratory assays. We performed logistic regression analysis to evaluate correlates with drug use. RESULTS: Among the 1935 MSM surveyed, 12.7% reported use of recreational drugs in the past six months. Rush poppers had become the most frequently used drug (10.6%). Risk factors associated with the use of recreational drugs included being unmarried, non-Han ethnicity, having high education level, seeking male sex partners via the internet, having multiple male sex partners, performing receptive role during anal sex, and having unprotected anal intercourse. Recreational drug use was significantly associated with higher risk of both HIV and syphilis infections (aOR:1.89, 95% CI:1.28-2.79; aOR:1.79, 95% CI:1.25-2.60, respectively). CONCLUSIONS: Recreational drug use is associated with increased risk of HIV and syphilis infections among MSM in Shenzhen. Rush poppers were the most popular recreational drug. This finding suggests the need for targeted prevention and behavioral intervention programs to control the recreational drug use, and to reduce HIV and other sexually transmitted diseases among MSM in Shenzhen and internationally.


Assuntos
Infecções por HIV/epidemiologia , Homossexualidade Masculina/estatística & dados numéricos , Drogas Ilícitas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Sífilis/epidemiologia , Adolescente , Adulto , Idoso , China/epidemiologia , Comorbidade , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
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