RESUMEN
GADD34 is a protein that is induced by stresses such as DNA damage. The function of mammalian GADD34 has been proposed by in vitro transfection, but its function in vivo has not yet been elucidated. Here we generated and analyzed GADD34 knockout mice. Despite their embryonic stage- and tissue-specific expressions, GADD34 knockout mice showed no abnormalities at fetal development and in early adult life. However, in GADD34-/- mouse embryonic fibroblasts (MEFs), recovery from a shutoff of protein synthesis was delayed when MEFs were exposed to endoplasmic reticulum (ER) stress. The phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) at Ser51 induced by thapsigargin or DTT was prolonged in GADD34-/- MEF, although following treatment with tunicamycin, the eIF2alpha phosphorylation level did not change in either GADD34+/+ or GADD34-/- cells. ER stress stimuli induced expressions of Bip (binding Ig protein) and CHOP (C/EBP homologous protein) in MEF of wild-type mice. These expressions were strongly reduced in GADD34-/- MEF, which suggests that GADD34 up-regulates Bip and CHOP. These results indicate that GADD34 works as a sensor of ER stress stimuli and recovers cells from shutoff of protein synthesis.
Asunto(s)
Retículo Endoplásmico/efectos de los fármacos , Proteínas de Choque Térmico , Biosíntesis de Proteínas , Proteínas/fisiología , Animales , Antígenos de Diferenciación , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Ditiotreitol/farmacología , Desarrollo Embrionario y Fetal , Chaperón BiP del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Feto/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Chaperonas Moleculares/metabolismo , Fosforilación , Proteína Fosfatasa 1 , Proteínas/genética , Tapsigargina/farmacología , Distribución Tisular , Factor de Transcripción CHOP , Factores de Transcripción/metabolismo , Tunicamicina/farmacologíaRESUMEN
The authors report a case of Q fever infection that caused acute exacerbation of chronic respiratory failure, which had developed as a sequela of pulmonary tuberculosis. This case was found on wide-ranging serological screening for respiratory infection performed in order to investigate the prevalence of Q fever in Japan. A 73-year-old man who had been treated for hypertension and sequelae of pulmonary tuberculosis was admitted to our hospital because of fever, productive cough, and dyspnea on effort. Hypoxia and right heart failure were detected on arterial blood analysis and ultrasonography. The acute exacerbation was triggered by respiratory infection and although the infection improved on azithromycin treatment after admission, respiratory failure continued for the period of admission. Home oxygen therapy was required for the management of chronic respiratory failure on discharge. Paired serum samples were tested for antibodies against Coxiella burnetii by indirect immunofluorescence, showing an elevated antibody titer in the convalescent phase. We believe that Q fever infection caused acute exacerbation of chronic respiratory failure, and that C. burnetii is an agent that might influence the clinical course of chronic respiratory failure.