RESUMO
In the HAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1-/- mice, with a doubling of the lifespan of Mlf1-/-/Hax1-/- animals compared to Hax1-/- animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.
Assuntos
Linfopenia/genética , Metaloproteases/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas/genética , Serina Endopeptidases/genética , Animais , Apoptose , Linfócitos B/metabolismo , Linfócitos B/patologia , Células COS , Proteínas de Ciclo Celular , Sobrevivência Celular , Chlorocebus aethiops , Proteínas de Ligação a DNA , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Deleção de Genes , Regulação da Expressão Gênica , Células HEK293 , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células K562 , Linfopenia/mortalidade , Linfopenia/patologia , Linfopenia/prevenção & controle , Metaloproteases/metabolismo , Camundongos , Proteínas Mitocondriais/metabolismo , Proteínas/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais , Análise de Sobrevida , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
OBJECTIVE: To compare the knee osteoarthritis (OA) models in rabbits by different concentrations of papain and provide data for exploring pathogenesis and treatments of this disease. METHODS: Sixty New Zealand white rabbits were randomly divided into four groups of 15 each and given injections into the right knee on days 1, 3 and 5 including intra-articular injections of 2%, 5% or 10% (w/v) papain and 0.03 mol/L L-cysteine at the dose of 0.1 ml/kg (experimental groups). The 0.9% NaCl (w/v) with a dose of 0.1 ml/kg were injected intra-articularly into the right knees of rabbits in the control group. The rabbits were sacrificed at 2, 4, 6 weeks respectively after the initiation of papain injection and these OA models were evaluated through recording the width of knee joint, performing the morphological observation and histological evaluation of articular cartilage and synovium. RESULTS: The degenerative changes were demonstrated in knee joints of rabbit in all experimental groups, such as thinner articular cartilage, fibrillation and destroyed cartilage matrix, and inflammation, proliferation, and degeneration of the synovial tissue. All these changes were much worse with increased concentration and prolonged observation time. CONCLUSION: Different severity of OA are established through intra-articular injections of 2%, 5% or 10% papain and 0.03 mol/L L-cysteine at the dose of 0.1 ml/kg. These models are of the characters of short period and a good reproducibility.
