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Journal of Environmental Pathology, Toxicology and Oncology

Impact factor: 1.246

ISSN Print: 0731-8898
ISSN Online: 2162-6537

Journal of Environmental Pathology, Toxicology and Oncology

DOI: 10.1615/JEnvironPatholToxicolOncol.v28.i1.30
pages 25-38

Siva-1 Promotes K-48 Polyubiquitination of TRAF2 and Inhibits TCR-Mediated Activation of NF-kappaB

Radhika Gudi
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
John Barkinge
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
Sarah Hawkins
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
Bellur Prabhakar
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
Prasad Kanteti
Department of Microbiology and Immunology, University of Illinois at Chicago

ABSTRACT

The proapoptotic protein Siva-1 plays an important role in some of the extrinsic and intrinsic apoptosis signaling pathways in cancer cells. Previously, we showed that Siva-1 inhibited the activity of the prosurvival transcription factor NF-κB. In the present study, upon TCR cross-linking of Jurkat T leukemia cells, we demonstrated that the inhibitory target of Siva-1 is upstream of the IKK complex in the NF-κB signaling pathway. Additionally, Siva-1 also suppressed the activity of another crucial transcription factor AP-1, and a common mediator of both these pathways is the adaptor protein TRAF2. Further, we observed that Siva-1 indeed interacted with TRAF2 and negatively regulated its activity by promoting K48-hnked polyubiquitination. Siva-1 specifically interacted with the ring finger domain of TRAF2, which is essential for its E3 hgase activity and its ability to subsequently activate NF-κB. TCR cross-linking of Jurkat T cells that lacked Siva-1 revealed significantly lowered K48- but elevated K63-ubiquitinated TRAF2 levels upon TCR cross-linking, suggesting that the differential pattern of ubiquitination in these cells essentially contributed to a robust and sustained activation of NF-κB. The above results demonstrated an important role for endogenous Siva-1 in negatively regulating NF-κB activation by targeting TRAF2.

KEY WORDS: Siva-1, NF-kappaB, AP-1, TRAF, K48, K63, NIK, TCR