CIAP2 inhibits anigen receptor signaling by targeting Bcl10 for degredation.
The cellular inhibitor of apoptosis 2 (cIAP2) is a RING-containing protein ubiquitin ligase. In a high percentage of mucosa-associated lymphoid tissue (MALT) lymphomas, cIAP2 is fused to MALT1/paracaspase as a result of the t(11;18)(q21;q21) translocation. The physiological function of cIAP2 in lymphocytes and how this function may be affected by the translocation are not well understood. We have shown that cIAP2 normally inhibits antigen receptor signaling by mediating the ubiquitination and degradation of Bcl10, a critical component for antigenic signaling to NF-kappaB. The cIAP2-MALT1 fusion protein lacks this E3 activity and is incapable of ubiquitinating Bcl10, likely causing enhanced Bcl10 expression. Furthermore, cIAP2-MALT1 and Bcl10 synergistically activate NF-kappaB. These results reveal a physiological function of cIAP2, identify Bcl10 upregulation as a unifying molecular mechanism for MALT lymphomas, and define the mechanism and effects of this upregulation in t(11;18)-positive MALT lymphomas.
Hu
Shimin
S
Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Alcivar
Allison
A
Qu
Like
L
Tang
Jun
J
Yang
Xiaolu
X
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000941:Antigens / Q000276:immunology*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D020169:Caspases / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein