dengue virus targets the adaptor protein mita to subvert host innate immunity登革病毒目标mita适配器蛋白质破坏宿主先天免疫.pdfVIP

Dengue Virus Targets the Adaptor Protein MITA to Subvert Host Innate Immunity 1 2 1 1 1 3 Chia-Yi Yu , Tsung-Hsien Chang , Jian-Jong Liang , Ruei-Lin Chiang , Yi-Ling Lee , Ching-Len Liao , Yi-Ling Lin1,3,4* 1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, 2 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, 3 Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, 4 Genomics Research Center, Academia Sinica, Taipei, Taiwan Abstract Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN). We found that activation of interferon regulatory factor 3 (IRF3) triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA) but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of 96 MITA was mapped to LRR Q G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enh