ABSTRACT
SARS coronavirus (SARS-CoV) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (IFN). Previous studies suggested that SARS-CoV papain-like protease (PLpro) inhibits activation of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism(s) used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro efficiently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain (PLpro-TM) from SARS-CoV inhibits STING/TBK1/IKKε-mediated activation of type I IFNs and disrupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBK1. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKKε, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activation of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is disrupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3-TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction with STING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.
Subject(s)
Humans , Dimerization , HEK293 Cells , I-kappa B Kinase , Metabolism , Interferon Regulatory Factor-3 , Metabolism , Interferon Type I , Metabolism , Membrane Proteins , Chemistry , Genetics , Metabolism , Papain , Metabolism , Peptide Hydrolases , Chemistry , Metabolism , Phosphorylation , Protein Binding , Protein Structure, Tertiary , Protein Serine-Threonine Kinases , Metabolism , Severe acute respiratory syndrome-related coronavirus , Signal Transduction , TNF Receptor-Associated Factor 3 , Metabolism , UbiquitinationABSTRACT
Objective To evaluate the techniques and efficacy of artery embolization in the treatment of benign prostatic hyperplasia(BHP).Methods This study included 12 patients(age range,61-82 years) who were diagnosed to have BHP by clinical manifestations,CT and B-ultrasound,with the disease course of 2-16 years.The relevant parameters were as follows:mean residual urine(RU) of 138 ml,Qmax of 9.6 ml/s,mean IPSS of 24.2 and QOL of 4.8.In these patients,the prostate blood-supply arteries were confirmed by super-selective arteriography,and were embolized by injection of PVA and Gelfoam via artery catheters.The pre-and post-operative IPSS,QOL,Qmax and RU were compared.Meanwhile the changes of prostate volume and blood supply were evaluated by CT and B-ultrasound.In addition,the change of urethral diameter was evaluated by urethrography.Results In the 12 patients,21 prostate blood-supply arteries were embolized,including 5 branches of internal iliac artery,9 branches of inferior vesical artery,5 branches of internal pudendal artery,2 branches of obturator artery.The arteries were embolized bilaterally in 9 patients and embolized unilaterally in 3 patients.Postoperatively,the mean IPSS was 4.8;QOL,1.3;Qmax,18.9 ml/s;RU,0-3 ml,which indicated that the urethral obstruction was obviously improved after operation.CT and B-ultrasound showed that the prostate volume was obviously decreased from 127 ml to 90 ml on average with a reduction rate of 71%,and the urethral stricture disappeared on X-ray examination.Color Doppler imaging showed that the blood supply inside the prostate was reduced.Conclusions The artery embolization for the treatment of BHP is a new method with several virtues of less trauma, marked effect,better safety and fewer complications.