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cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas
Shimin Hu, … , James L. Riley, Xiaolu Yang
Shimin Hu, … , James L. Riley, Xiaolu Yang
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):174-181. https://doi.org/10.1172/JCI25641.
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Research Article Oncology

cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas

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Abstract

The pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphomas is associated with independent chromosomal translocations that lead to the upregulation of either BCL10 or MALT1 or the generation of a fusion protein, cIAP2-MALT1. While both BCL10 and MALT1 are critically involved in antigen receptor–mediated NF-κB activation, the role of cIAP2 is not clear. Here we show that cIAP2 is a ubiquitin ligase (E3) of BCL10 and targets it for degradation, inhibiting antigen receptor–mediated cytokine production. cIAP2-MALT1 lacks E3 activity, and concomitantly, the BCL10 protein is stabilized in MALT lymphomas harboring this fusion. Furthermore, BCL10 and cIAP2-MALT1 synergistically activate NF-κB. These results reveal cIAP2 as an inhibitor of antigenic signaling and implicate its dysfunction in MALT lymphomas.

Authors

Shimin Hu, Ming-Qing Du, Sun-Mi Park, Allison Alcivar, Like Qu, Sanjeev Gupta, Jun Tang, Mathijs Baens, Hongtao Ye, Tae H. Lee, Peter Marynen, James L. Riley, Xiaolu Yang

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Figure 4

cIAP2 inhibits antigen receptor signaling via BCL10 degradation.

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cIAP2 inhibits antigen receptor signaling via BCL10 degradation.
(A) Deg...
(A) Degradation of BCL10 in response to antigenic stimulation. Human primary T and B cells were treated with anti–CD3/CD28 and anti–IgM/CD40, respectively, for the indicated durations. (B) Ubiquitination of BCL10 after antigen receptor cross-linking in primary T lymphocytes. Human primary T cells were treated with anti–CD3/CD28 and TNF-α as indicated. BCL10 was immunoprecipitated from cell lysates and analyzed by Western blot. (C) cIAP2 accelerates the degradation of endogenous BCL10. Human CD4+ cells were transfected with a control GFP-expressing plasmid (C) or cIAP2 plasmid. Cells were then treated with anti–CD3/CD28 beads for the indicated durations. The transfection efficiency was approximately 80% based on GFP expression. (D) cIAP2Δ and cIAP2-MALT1 stabilize BCL10. Human primary CD4+ T cells were transfected with GFP (C), cIAP2Δ, or cIAP2-MALT1, plus murine CD8. Transfected live cells were purified using anti–murine CD8 beads. (E) Effects of cIAP2Δ on the degradation of BCL10. Human primary CD4+ T cells were transfected with HA-BCL10 together with GFP (C) or cIAP2Δ. Cells were then treated with anti–CD3/CD28 for the indicated durations, and the levels of HA-BCL10 were analyzed by Western blot with anti-HA antibody. (F) cIAP2 inhibits anti–CD3/CD28–mediated IL-2 induction. Human primary CD4+ T cells were transfected with GFP, cIAP2, cIAP2Δ, or cIAP2-MALT1, plus m/hCD28. Cells were stimulated with anti–human CD3 and anti–murine CD28 beads for 8 hours or left untreated. The fold IL-2 induction relative to untreated cells (UT) is shown. The data are representative of 3 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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