Abstract
Antigen receptors on B and T lymphocytes utilize specific adapter and scaffolding proteins to relay antigen recognition at the cell surface to the activation of downstream signaling pathways. One central pathway that is induced upon TCR and BCR ligation cumulates in the activation of NF-κB. This cascade is essential for the elicitation of proper immune responses but when aberrantly activated can also promote diseases including malignancy. Recent work identified the CARD protein BCL10 and the paracaspase MALT1 as key regulators of antigen receptor mediated NF-κB induction. The genes encoding these proteins were originally identified from recurrent chromosomal translocations in mucosa associated lymphoid tissue (MALT) lymphoma associated with advanced disease. In physiological adaptive immune responses antigen receptor proximal signaling and PKC activation induces recruitment of BCL10 and MALT1 to the scaffold protein CARMA1 at the immunoreceptor. Here BCL10 and MALT1 cooperate directly to assemble a multi protein complex that mediates lysine-63-linked ubiquitination of NEMO, the regulatory subunit of the I B kinase (IKK). This mechanism induces signal specific IKK activation, leading to phosphorylation and degradation of the NF-κB inhibitor IκB-α and finally results in controlled activation of NF-κB. However chromosomal translocations in MALT lymphoma uncouple BCL10 or MALT1 from upstream stimuli and promote antigen independent lymphoma growth with tumor progression. This review discusses the mechanisms of BCL10 and MALT1 signal transduction and their critical role in lymphocyte physiology and neoplasia.
Keywords: bcl, malt1, nf-κb, cell survival, signal transduction, lymphoma
3