West Nile virus and dengue virus capsid protein negates the antiviral activity of human Sec3 protein through the proteasome pathway
West Nile virus and dengue virus capsid protein negates the antiviral activity of human Sec3 protein through the proteasome pathway
复制标题
DOI：
10.1111/cmi.12143
复制
发表时间：
2013-10-01
影响因子：
3.4
通讯作者：
Ng, Mah-Lee
中科院分区：
文献类型：
--
作者：
Bhuvanakantham, Raghavan;Ng, Mah-Lee
黄病毒衣壳（C）蛋白是病毒颗粒的关键结构组分。C蛋白在节肢动物传播的黄病毒的发病机制中的非结构性作用还不清楚。本研究表明，西尼罗病毒（WNV）和登革病毒（DENV）利用C蛋白激活20 S蛋白酶体的糜蛋白酶样蛋白水解功能，在转录后水平降低人Sec 3 p（hSec 3 p）的水平。突变研究证实，WNV C蛋白的第14，109-114位氨基酸和DENV C蛋白的第13，102-107位氨基酸在激活20 S蛋白酶体的蛋白水解功能中发挥重要作用。C蛋白的14位（WNV）和13位（DENV）氨基酸残基对C蛋白与hSec 3 p的结合非常重要，C蛋白与hSec 3 p之间的物理相互作用是执行hSec 3 p降解的必要条件。降解hSec 3 p所需的降解基序位于WNV C蛋白的氨基酸残基109-114和DENV C蛋白的氨基酸残基102-107之间。蛋白酶体、hSec 3 p结合基序和C蛋白上的降解基序必须是完整的以有效地生产黄病毒。DENV的临床分离株在操纵蛋白酶体和降低hSec 3 p水平方面表现出更显著的效果。该研究描述了C蛋白的非结构功能，其通过加速hSec 3 p的降解和促进延伸因子1与黄病毒RNA基因组的有效结合来帮助黄病毒抵消hSec 3 p的抗病毒活性。
Flavivirus capsid (C) protein is a key structural component of virus particles. The non-structural role of C protein in the pathogenesis of arthropod-borne flaviviruses is not clearly deciphered. This study showed that West Nile virus (WNV) and dengue virus (DENV) utilized C protein to reduce human Sec3p (hSec3p) levels at post-transcriptional level through activation of chymotrypsin-like proteolytic function of 20S proteasome. Mutagenesis studies confirmed amino acids 14, 109-114 of WNV C protein and 13, 102-107 of DENV C protein played an important role in activating the proteolytic function of 20S proteasome. Amino acid residues at 14 (WNV) and 13 (DENV) of C protein were important for C protein-hSec3p binding and physical interaction between C protein and hSec3p was essential to execute hSec3p degradation. Degradation motif required to degrade hSec3p resided between amino acid residues 109-114 of WNV C protein and 102-107 of DENV C protein. Proteasomes, hSec3p binding motif and degradation motif on C protein must be intact for efficient flavivirus production. Clinical isolates of DENV showed more pronounced effect in manipulating the proteasomes and reducing hSec3p levels. This study portrayed the non-structural function of C protein that helped the flavivirus to nullify the antiviral activity of hSec3p by accelerating its degradation and facilitating efficient binding of elongation factor 1 with flaviviral RNA genome.