cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas.
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-kappaB 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-kappaB. These results reveal cIAP2 as an inhibitor of antigenic signaling and implicate its dysfunction in MALT lymphomas.
Hu
Shimin
S
Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Du
Ming-Qing
MQ
Park
Sun-Mi
SM
Alcivar
Allison
A
Qu
Like
L
Gupta
Sanjeev
S
Tang
Jun
J
Baens
Mathijs
M
Ye
Hongtao
H
Lee
Tae H
TH
Marynen
Peter
P
Riley
James L
JL
Yang
Xiaolu
X
D020169:Caspases; D002460:Cell Line; D016207:Cytokines / Q000276:immunology*; D050939:Gene Fusion; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014178:Translocation, Genetic
D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein