Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase.
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.
Elliott
Joanne
J
Molecular Immunity, Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University Belfast, Whitla Medical Building, 97 Lisburn Rd., Belfast BT9 7BL, Northern Ireland.
Lynch
Oonagh T
OT
Suessmuth
Yvonne
Y
Qian
Ping
P
Boyd
Caroline R
CR
Burrows
James F
JF
Buick
Richard
R
Stevenson
Nigel J
NJ
Touzelet
Olivier
O
Gadina
Massimo
M
Power
Ultan F
UF
Johnston
James A
JA
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D000075065:Elongin; D006801:Humans; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D044842:Cullin Proteins; C000616395:ELOC protein, human; D000075065:Elongin; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D014157:Transcription Factors; D025801:Ubiquitin; D017361:Viral Nonstructural Proteins; D046988:Proteasome Endopeptidase Complex