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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 3

cIAP2 is an E3 of BCL10.

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cIAP2 is an E3 of BCL10.
(A) cIAP2 mediates BCL10 modification in mammal...
(A) cIAP2 mediates BCL10 modification in mammalian cells. BCL10-HA was expressed alone or together with the indicated E3s in the presence of HA-ubiquitin. Varying amounts of BCL10-HA plasmid were used for transfection to ensure similar expression levels among different samples. Anti-FLAG immunoprecipitates and extracts were analyzed by Western blot with the indicated antibodies. This band is recognized by anti-BCL10 antibody and not by anti-HA antibody (data not shown). (B and C) cIAP2-mediated BCL10 ubiquitination in cells. (B) 293T cells were transfected with GST-BCL10-HA, FLAG-cIAP2, and FLAG-cIAP2Δ as indicated, and cell extracts were incubated with anti-FLAG beads. The immunoprecipitates and extracts were analyzed by Western blot. (C) 293T cells were transfected with GST-BCL10-FLAG and/or GST-cIAP2. The cell extracts were incubated with either anti-FLAG beads or glutathione beads (GTN, for GST tagged proteins), and the precipitates and extracts were analyzed by Western blot. (D) Ubiquitination of BCL10 by cIAP2 in vitro. Recombinant GST-BCL10 was incubated with recombinant ubiquitin, cIAP2 (lanes 3, 5, and 6), or cIAP2Δ (lane 4), and recombinant E1 and/or E2, as indicated. The samples were analyzed by Western blot with anti-BCL10 (top) or anti-cIAP2 (bottom) antibody. cIAP2 did not ubiquitinate GST (data not shown). (E) Wild-type cIAP2, but not the RING deletion mutant, induces BCL10 degradation. BCL10-HA was coexpressed with increasing amounts of FLAG-cIAP2 or FLAG-cIAP2Δ. Endo., endogenous; F, FLAG; G, GST; Ub, ubiquitin.

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

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