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Helmholtz Zentrum München
Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.
The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.
The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic
target for lymphomas and other diseases.
Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.
“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”
The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.
In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.
If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.
The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.
If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.
“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.
In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.
In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.
