RESUMO
Establishing the balance between positive and negative innate immune mechanisms is crucial for maintaining homeostasis. Here we uncover the regulatory crosstalk between two previously unlinked innate immune receptor families: RIG-I, an anti-viral cytosolic receptor activated type I interferon production, and NLR (nucleotide-binding domain, leucine repeat domain-containing protein). We show that NLRP12 dampens RIG-I-mediated immune signaling against RNA viruses by controlling RIG-I's association with its adaptor MAVS. The nucleotide-binding domain of NLRP12 interacts with the ubiquitin ligase TRIM25 to prevent TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. NLRP12 also enhances RNF125-mediated, Lys48-linked degradative ubiquitination of RIG-I. Vesicular stomatitis virus (VSV) infection downregulates NLRP12 expression to allow RIG-I activation. Myeloid-cell-specific Nlrp12-deficient mice display a heightened interferon and TNF response and are more resistant to VSV infection. These results indicate that NLRP12 functions as a checkpoint for anti-viral RIG-I activation.
Assuntos
Proteína DEAD-box 58/imunologia , Proteínas de Ligação a DNA/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Fatores de Transcrição/imunologia , Animais , Proteína DEAD-box 58/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Interferons/genética , Interferons/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Fatores de Transcrição/genética , UbiquitinaçãoAssuntos
Encondromatose/diagnóstico por imagem , Encondromatose/cirurgia , Articulações dos Dedos/cirurgia , Transplante Ósseo/métodos , Curetagem/métodos , Articulações dos Dedos/diagnóstico por imagem , Articulações dos Dedos/fisiopatologia , Hemangioma/diagnóstico por imagem , Hemangioma/fisiopatologia , Hemangioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/fisiopatologia , Neoplasias Cutâneas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: We evaluated the clinicopathological associations and prognostic implications of promyelocytic leukemia gene (PML) expressions in patients with esophageal squamous cell carcinomas (ESCC) receiving primary surgery. METHODS: Expression patterns of PML and tumor protein 53 (TP53) of 132 cases of ESCC were evaluated by immunohistochemistry and correlated with clinicopathological parameters. The Cox proportional hazards model was used to determine the prognostic influence of clinicopathological factors on progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-two cases (31.82%) were classified as lost expression of PML, 25 (18.94%) as focally positive, and 65 (49.24%) as diffusely expressed. Sixty-three cases (47.73%) were classified as over-expression of TP53. High expression of TP53 and down-regulation of PML were often found in advanced disease; and, in together with high pathological staging, grading, and positive margin, were associated with poor survival. However, only tumor differentiation (P = 0.016), distant metastasis (P = 0.001), and PML expression (P = 0.001) could act as independent prognostic factors for PFS, and LN metastasis (P = 0.004), TP53 (P = 0.006), and PML expression (P = 0.029) were identified as independent prognostic factors for OS in multivariate analysis. CONCLUSIONS: Our study demonstrated PML protein as an independent prognostic marker for patients with ESCC receiving primary surgery.