Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha.
Smac mimetics induce apoptosis synergistically with TNF-alpha by triggering the formation of a caspase-8-activating complex containing receptor interacting protein kinase-1 (RIPK1). Caspase inhibitors block this form of apoptosis in many types of cells. However, in several other cell lines, caspase inhibitors switch the apoptotic response to necrosis. A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. The kinase activity of RIP3 is essential for necrosis execution. Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. Embryonic fibroblasts from RIP3 knockout mice are resistant to necrosis and RIP3 knockout animals are devoid of inflammation inflicted tissue damage in an acute pancreatitis model. These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines.
He
Sudan
S
Graduate Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Wang
Lai
L
Miao
Lin
L
Wang
Tao
T
Du
Fenghe
F
Zhao
Liping
L
Wang
Xiaodong
X
D000818:Animals; D045744:Cell Line, Tumor; D002108:Ceruletide; D006801:Humans; D051379:Mice; D009154:Mutation; D009336:Necrosis; D010195:Pancreatitis / Q000139:chemically induced / Q000503:physiopathology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D002108:Ceruletide; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse