Vaccinia virus protein F1L is a caspase-9 inhibitor.
Apoptosis plays important roles in host defense, including the elimination of virus-infected cells. The executioners of apoptosis are caspase family proteases. We report that vaccinia virus-encoded F1L protein, previously recognized as anti-apoptotic viral Bcl-2 family protein, is a caspase-9 inhibitor. F1L binds to and specifically inhibits caspase-9, the apical protease in the mitochondrial cell death pathway while failing to inhibit other caspases. In cells, F1L inhibits apoptosis and proteolytic processing of caspases induced by overexpression of caspase-9 but not caspase-8. An N-terminal region of F1L preceding the Bcl-2-like fold accounts for caspase-9 inhibition and significantly contributes to the anti-apoptotic activity of F1L. Viral F1L thus provides the first example of caspase inhibition by a Bcl-2 family member; it functions both as a suppressor of proapoptotic Bcl-2 family proteins and as an inhibitor of caspase-9, thereby neutralizing two sequential steps in the mitochondrial cell death pathway.
Zhai
Dayong
D
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Yu
Eric
E
Jin
Chaofang
C
Welsh
Kate
K
Shiau
Chung-wei
CW
Chen
Lili
L
Salvesen
Guy S
GS
Liddington
Robert
R
Reed
John C
JC
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053181:Caspase 8 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D002417:Cattle; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014616:Vaccinia virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D061945:Caspase Inhibitors; C507356:F1L protein, vaccinia virus; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D014764:Viral Proteins; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9