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First published online 7 July 2009
doi: 10.1242/jcs.049940

Journal of Cell Science 122, 2651-2661 (2009)
Published by The Company of Biologists 2009
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Research Article

Siva1 is a XIAP-interacting protein that balances NF{kappa}B and JNK signalling to promote apoptosis

Ulrike Resch1,*, Yvonne M. Schichl1, Gabriele Winsauer1, Radhika Gudi2, Kanteti Prasad2 and Rainer de Martin1

1 Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Lazarettg. 19, A-1090, Vienna, Austria
2 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA

* Author for correspondence (e-mail: Ulrike.resch{at}meduniwien.ac.at)

Accepted 22 April 2009

XIAP is known as a potent inhibitor of apoptosis, but in addition is involved in cellular signalling, including the NF{kappa}B, JNK and TGFβ pathways. Our search for XIAP-interacting partners led us to Siva1, a proapoptotic protein that is known to play a role in T-cell apoptosis through a caspase-dependent mitochondrial pathway. The interaction sites between XIAP and Siva1 were mapped to the RING domain of XIAP and the N-terminal, SAH-containing and death-homology-region-containing domains of Siva1. Co-immunoprecipitation experiments showed that XIAP, Siva1 and TAK1 form a ternary complex in Jurkat T cells. Reporter-gene analysis revealed that Siva1 inhibits XIAP- and TAK1-TAB1-mediated NF{kappa}B activation. By contrast, Siva1 increased XIAP- and TNF{alpha}-mediated AP1 activity and prolonged TNF{alpha}-induced JNK activation, whereas knock down of Siva1 resulted in reduced JNK activation. This suggests that Siva1 differentially modulates signalling by JNK and NF{kappa}B and shifts the balance between these pathways towards enhanced JNK activation, a situation that promotes apoptosis. Ectopically expressed Siva1 increased caspase-3 activity, which was inhibited by XIAP in a ubiquitin-ligase-dependent manner. In line with this, Siva1 was lysine-48-linked polyubiquitylated by XIAP. Our findings suggest that, via physical interaction with XIAP and TAK1, Siva1 diminishes NF{kappa}B and enhances JNK activity to favour apoptosis.

Key words: Siva1, XIAP, TAK1, JNK, Apoptosis


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