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Molecular and Cellular Biology, June 2004, p. 5235-5248, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5235-5248.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ABIN-2 Forms a Ternary Complex with TPL-2 and NF-{kappa}B1 p105 and Is Essential for TPL-2 Protein Stability{dagger}

V. Lang,1,{ddagger} A. Symons,1,{ddagger} S. J. Watton,1,{ddagger} J. Janzen,1 Y. Soneji,1 S. Beinke,1 S. Howell,2 and S. C. Ley1*

Divisions of Immune Cell Biology,1 Protein Structure, National Institute for Medical Research, London NW7 1AA, United Kingdom2

Received 20 November 2003/ Returned for modification 23 December 2003/ Accepted 16 March 2004

NF-{kappa}B1 p105 forms a high-affinity, stoichiometric interaction with TPL-2, a MEK kinase essential for TLR4 activation of the ERK mitogen-activated protein kinase cascade in lipopolysaccharide (LPS)-stimulated macrophages. Interaction with p105 is required to maintain TPL-2 metabolic stability and also negatively regulates TPL-2 MEK kinase activity. Here, affinity purification identified A20-binding inhibitor of NF-{kappa}B 2 (ABIN-2) as a novel p105-associated protein. Cotransfection experiments demonstrated that ABIN-2 could interact with TPL-2 in addition to p105 but preferentially formed a ternary complex with both proteins. Consistently, in unstimulated bone marrow-derived macrophages (BMDMs), a substantial fraction of endogenous ABIN-2 was associated with both p105 and TPL-2. Although the majority of TPL-2 in these cells was complexed with ABIN-2, the pool of TPL-2 which could activate MEK after LPS stimulation was not, and LPS activation of TPL-2 was found to correlate with its release from ABIN-2. Depletion of ABIN-2 by RNA interference dramatically reduced steady-state levels of TPL-2 protein without affecting levels of TPL-2 mRNA or p105 protein. In addition, ABIN-2 increased the half-life of cotransfected TPL-2. Thus, optimal TPL-2 stability in vivo requires interaction with ABIN-2 as well as p105. Together, these data raise the possibility that ABIN-2 functions in the TLR4 signaling pathway which regulates TPL-2 activation.

* Corresponding author. Mailing address: Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 44-8816-2463. Fax: 44-8906-4477. E-mail: sley{at}nimr.mrc.ac.uk.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} V.L., A.S., and S.J.W. contributed equally to this work.

Molecular and Cellular Biology, June 2004, p. 5235-5248, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5235-5248.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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