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

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

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 2

Association of cIAP2 and BCL10.

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Association of cIAP2 and BCL10. (A) Schematic representation of cIAP2 an...
(A) Schematic representation of cIAP2 and its mutants. The amino acids present in each protein are marked. (B) Interaction of cIAP2 and BCL10 in mammalian cells. 293T cells were transfected with the indicated combinations of plasmids. Cell lysates of the transfected cultures were immunoprecipitated (IP) with an anti-FLAG mAb, and the immunoprecipitated proteins and cell extracts were analyzed by Western blot (WB) with the indicated antibodies. Molecular weight standards (in kDa) are shown on the left. F, FLAG. (C) Interaction of cIAP2 and BCL10 in vitro. In vitro–translated, 35S-labeled cIAP2 proteins were incubated with either GST protein or a GST fusion of BCL10 immobilized on agarose beads. The bound proteins and 5% of the input 35S-cIAP2 proteins were analyzed by SDS-PAGE and autoradiography. (D) Association of endogenous BCL10 and cIAP2. Extracts from human primary T cells treated with or without PMA plus ionomycin were immunoprecipitated with an anti-BCL10 antibody or an isotype-matching control antibody. The immunoprecipitated proteins and a portion of the input proteins were analyzed by Western blot. (E) Phosphorylation of BCL10 in mammalian cells. Extracts from BCL10-HA–transfected 293T cells were treated with phosphatase (PPase) (+) or left untreated (–).