Auto-ubiquitination-induced degradation of MALT1-API2 prevents BCL10 destabilization in t(11;18)(q21;q21)-positive MALT lymphoma.
BACKGROUND
The translocation t(11;18)(q21;q21) is the most frequent chromosomal aberration associated with MALT lymphoma and results in constitutive NF-kappaB activity via the expression of an API2-MALT1 fusion protein. The properties of the reciprocal MALT1-API2 were never investigated as it was reported to be rarely transcribed.


RESULTS
Our data indicate the presence of MALT1-API2 transcripts in the majority of t(11;18)(q21;q21)-positive MALT lymphomas. Based on the breakpoints in the MALT1 and API2 gene, the MALT1-API2 protein contains the death domain and one or both immunoglobulin-like domains of MALT1 (approximately 90% of cases)--mediating the possible interaction with BCL10--fused to the RING domain of API2. Here we show that this RING domain enables MALT1-API2 to function as an E3 ubiquitin ligase for BCL10, inducing its ubiquitination and proteasomal degradation in vitro. Expression of MALT1-API2 transcripts in t(11;18)(q21;q21)-positive MALT lymphomas was however not associated with a reduction of BCL10 protein levels.


CONCLUSIONS
As we observed MALT1-API2 to be an efficient target of its own E3 ubiquitin ligase activity, our data suggest that this inherent instability of MALT1-API2 prevents its accumulation and renders a potential effect on MALT lymphoma development via destabilization of BCL10 unlikely.
Noels
Heidi
H
Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium.
Somers
Riet
R
Liu
Hongxiang
H
Ye
Hongtao
H
Du
Ming-Qing
MQ
De Wolf-Peeters
Christiane
C
Marynen
Peter
P
Baens
Mathijs
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11; D002887:Chromosomes, Human, Pair 18; D006801:Humans; D006868:Hydrolysis; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D054875:Ubiquitination
C415943:API2-MALT1 fusion protein, human; D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D015514:Oncogene Proteins, Fusion; D046988:Proteasome Endopeptidase Complex