Respiratory syncytial virus NS1 protein degrades STAT2 by using the elongin-cullin E3 ligase

被引:153
作者
Elliott, Joanne
Lynch, Oonagh T.
Suessmuth, Yvonne
Qian, Ping
Boyd, Caroline R.
Burrows, James F.
Buick, Richard
Stevenson, Nigel J.
Touzelet, Olivier
Gadina, Massimo
Power, Ultan F.
Johnston, James A.
机构
[1] Queens Univ Belfast, CCRCB, Infect & Immun Grp, Belfast BT9 7BL, Antrim, North Ireland
[2] Fusion Antibodies Ltd, Belfast BT1 2WD, Antrim, North Ireland
基金
英国惠康基金;
关键词
D O I
10.1128/JVI.02303-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Respiratory syncytial virus (RSV) infection causes bronchiolitis and pneumonia in infants. RSV has a linear single-stranded RNA genome encoding 11 proteins, 2 of which are nonstructural (NS1 and NS2). RSV specifically downregulates STAT2 protein expression, thus enabling the virus to evade the host type I interferon response. Degradation of STAT2 requires proteasomal activity and is dependent on the expression of RSV NS1 and NS2 (NS1/2). Here we investigate whether RSV NS proteins can assemble ubiquitin ligase (E3) enzymes to target STAT2 to the proteasome. We demonstrate that NS1 contains elongin C and cullin 2 binding consensus sequences and can interact with elongin C and cullin 2 in vitro; therefore, NS1 has the potential to act as an E3 ligase. By knocking down expression of specific endogenous E3 ligase components using small interfering RNA, NS1/2, or RSV-induced STAT2, degradation is prevented. These results indicate that E3 ligase activity is crucial for the ability of RSV to degrade STAT2. These data may provide the basis for therapeutic intervention against RSV and/or logically designed live attenuated RSV vaccines.
引用
收藏
页码:3428 / 3436
页数:9
相关论文
共 37 条
[1]   The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5 [J].
Andrejeva, J ;
Poole, E ;
Young, DF ;
Goodbourn, S ;
Randall, RE .
JOURNAL OF VIROLOGY, 2002, 76 (22) :11379-11386
[2]  
Ausubel FM, 1995, SHORT PROTOCOLS MOL
[3]   Inhibition of respiratory viruses by nasally administered siRNA [J].
Bitko, V ;
Musiyenko, A ;
Shulyayeva, O ;
Barik, S .
NATURE MEDICINE, 2005, 11 (01) :50-55
[4]   The Yin and Yang of type I interferon activity in bacterial infection [J].
Decker, T ;
Müller, M ;
Stockinger, S .
NATURE REVIEWS IMMUNOLOGY, 2005, 5 (09) :675-687
[5]   Expression and characterisation of the NS1 and NS2 proteins of respiratory syncytial virus [J].
Evans, JE ;
Cane, PA ;
Pringle, CR .
VIRUS RESEARCH, 1996, 43 (02) :155-161
[6]   Paramyxovirus the interferon strategies for evading response [J].
Gotoh, B ;
Komatsu, T ;
Takeuchi, K ;
Yokoo, J .
REVIEWS IN MEDICAL VIROLOGY, 2002, 12 (06) :337-357
[7]   Silencing STATs: lessons from paramyxovirus interferon evasion [J].
Horvath, CM .
CYTOKINE & GROWTH FACTOR REVIEWS, 2004, 15 (2-3) :117-127
[8]  
Horvath CM, 1996, MOL CELL BIOL, V16, P6957
[9]   The von Hippel-Lindau tumor suppressor protein [J].
Ivan, M ;
Kaelin, WG .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2001, 11 (01) :27-34
[10]   Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex [J].
Iwai, K ;
Yamanaka, K ;
Kamura, T ;
Minato, N ;
Conaway, RC ;
Canaway, JW ;
Klausner, RD ;
Pause, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (22) :12436-12441