the c proteins of human parainfluenza virus type 1 block ifn signaling by binding and retaining stat1 in perinuclear aggregates at the late endosome人类副流感病毒病毒1型块的c蛋白干扰素信号通过绑定在细胞核周围的总量和留住stat1晚期内体.pdf

The C Proteins of Human Parainfluenza Virus Type 1 Block IFN Signaling by Binding and Retaining Stat1 in Perinuclear Aggregates at the Late Endosome Henrick Schomacker, Rebecca M. Hebner, Jim Boonyaratanakornkit, Sonja Surman, Emerito Amaro- Carambot, Peter L. Collins, Alexander C. Schmidt* RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America Abstract Interferons (IFNs) play a crucial role in the antiviral immune response. Whereas the C proteins of wild-type human parainfluenza virus type 1 (WT HPIV1) inhibit both IFN-b induction and signaling, a HPIV1 mutant encoding a single amino acid substitution (F170S) in the C proteins is unable to block either host response. Here, signaling downstream of the type 1 IFN receptor was examined in Vero cells to define at what stage WT HPIV1 can block, and F170S HPIV1 fails to block, IFN signaling. WT HPIV1 inhibited phosphorylation of both Stat1 and Stat2, and this inhibition was only slightly reduced for F170S HPIV1. Degradation of Stat1 or Stat2 was not observed. The HPIV1 C proteins were found to accumulate in the perinuclear space, often forming large granules, and co-localized with Stat1 and the cation-independent mannose 6- phosphate receptor (M6PR) that is a marker for late endosomes. Upon stimulation with IFN-b, both the WT and F170S C proteins remained in the perinuclear space, but only the WT C proteins prevented Stat1 translocation to the nucleus. In addition, WT HPIV1 C proteins, but not F170S C proteins, co-immunoprecipitated both phosphorylated and unphosphorylated Stat1. Our findings suggest that the WT HPIV1 C proteins form a stable complex with Stat1