ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis.
We have previously described a new aspect of the Inhibitor of Apoptosis (IAP) family of proteins anti-apoptotic activity that involves the TAK1/JNK1 signal transduction pathway (1,2). Our findings suggest the existence of a novel mechanism that regulates the anti-apoptotic activity of IAPs that is separate from caspase inhibition but instead involves TAK1-mediated activation of JNK1. In a search for proteins involved in the XIAP/TAK1/JNK1 signaling pathway we isolated by yeast two-hybrid screening a novel X chromosome-linked IAP (XIAP)-interacting protein that we called ILPIP (hILP-Interacting Protein). Whereas ILPIP moderately activates JNK family members when expressed alone, it strongly enhances XIAP-mediated activation of JNK1, JNK2, and JNK3. The expression of a catalytically inactive mutant of TAK1 blocked XIAP/ILPIP synergistic activation of JNK1 thereby implicating TAK1 in this signaling pathway. ILPIP moderately protects against interleukin-1beta converting enzyme- or Fas-induced apoptosis and significantly potentiates the anti-apoptotic activity of XIAP. In vivo co-precipitation experiments show that both ILPIP and XIAP interact with TAK1 and tumor necrosis factor receptor-associated factor 6. Finally, expression of ILPIP did not affect the ability of XIAP to inhibit caspase activation, further supporting the idea that XIAP protection against apoptosis is achieved by two separate mechanisms: one requiring JNK1 activation and a second involving caspase inhibition.
Sanna
M Germana
MG
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
da Silva Correia
Jean
J
Luo
Ying
Y
Chuang
Betty
B
Paulson
Lorien M
LM
Nguyen
Binh
B
Deveraux
Quinn L
QL
Ulevitch
Richard J
RJ
D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D020930:MAP Kinase Kinase Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D020798:Two-Hybrid System Techniques; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099151:MAP Kinase Kinase Kinase 7
D020169:Caspases; D020930:MAP Kinase Kinase Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099151:MAP Kinase Kinase Kinase 7; C496866:XIAP protein, human