The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferation.

Caspase-8, an initiator caspase involved in lymphocyte apoptosis, is paradoxically required for lymphocyte proliferation. It is not understood how caspase-8 is controlled during antigenic signaling to allow for activation while averting the triggering of apoptosis. Here, we show that caspase-8 undergoes limited activation upon antigenic stimulation, and this activation is dependent on the paracaspase MALT1. The paracaspase domain of MALT1, in a protease-independent manner, induces caspase-8 activation through direct association. MALT1 diminishes the activation of apoptotic effector caspases, but it does not alter the activity of caspase-8 toward c-FLIP(L), which is required for antigenic signaling. Mutants of MALT1 that fail to activate caspase-8 and permit c-FLIP(L) cleavage cannot facilitate NF-kappaB activation or IL-2 induction. Our results reveal a mechanism that utilizes a protease potentially deadly to the cell for proliferative signaling and demonstrate a functional connection between the caspase and paracaspase families to enable nonapoptotic processes.

Lys63-linked polyubiquitin chains: linking more than just ubiquitin.

Polyubiquitin chains linked through the Lys48 residue of ubiquitin are most commonly associated with targeting proteins for proteosomal degradation. In contrast, polyubiquitin chains linked through the Lys63 residue of ubiquitin are associated with nonproteolytic functions such as signal transduction. The mechanism by which Lys63-linked polyubiquitin chains participate in signaling cascades has yet to be determined, but two recent publications (Wu et al., Nat Cell Bio 2006; 8:398-406 and Ea et al., Mol Cell 2006; 22:245-57) shed light on how this distinctive modification functions in NFkappaB activation by TNFalpha. Upon stimulation with TNFalpha, RIP1 undergoes Lys63-linked polyubiquitination. The polyubiquitin chain on RIP1 is recognized and bound by NEMO, the regulatory subunit of the IKK complex, and this binding is essential for NFkappaB activation by TNFalpha. Thus, Lys63-linked polyubiquitin chains critically connect components of NFkappaB signaling in a highly regulated manner.

A novel fusion of the MALT1 gene and the microtubule-associated protein 4 (MAP4) gene occurs in diffuse large B-cell lymphoma.

Rearrangements of the MALT1 gene by the t(11;18)(q21;q21) and t(14;18)(q32;q21) are the most frequent structural chromosomal abnormalities in MALT lymphomas. These translocations lead to fusions of BIRC3-MALT1 and IGH-MALT1 respectively, and activate the NF-kappaB pathway. Among 122 diffuse large B-cell lymphomas and 28 Burkitt's lymphomas screened by interphase FISH, we found two cases with a break within MALT1, but without a t(11;18) or a t(14;18). Molecular genetic analyses in one of these cases revealed a novel "in frame" fusion of exon 9 of MALT1 and exon 9 of the microtubule-associated protein 4 (MAP4) gene. The translocation was accompanied by a deletion of MALT1 sequences distal to the breakpoint including the caspase-like domain, which is essential for activation of NF-kappaB. As a result of the deletion, the reciprocal 5'MAP4-3'MALT1 transcript was not present, demonstrating that the 5'MALT1-3'MAP4 fusion represents the pathogenetically relevant transcript. Immunohistochemistry with amino-terminal and carboxy-terminal MALT1 antibodies, indicated a strong expression of the chimeric MALT1-MAP4 protein. Moreover, NF-kappaB activation was not increased in this case as shown by the levels of IkappaBalpha phosphorylation and NEMO ubiquitination. Our data demonstrate that the pathogenetic consequences of the novel MALT1-MAP4 fusion are different from those of the known MALT1-associated chromosomal rearrangements and do not involve NF-kappaB activation.

Lymphocyte life and death: the caspase-8 connection.

Caspase-8 plays an important role in death receptor-mediated apoptosis. In contrast to its apoptotic function, recent studies have suggested caspase-8 also plays a role in the immune response, as caspase-8 is essential for lymphocyte proliferation in response to antigen stimulation. In the March 2005 issue of Science (2005; 307:1465-8), Su et al. provide compelling evidence supporting a role for caspase-8 in antigen receptor-induced NF-kappaB activation. They identified caspase-8 as an essential component in the activation of the IKK complex, linking IKK to the upstream Bcl10-MALT1 complex. Intriguingly, they demonstrated that it is not only the physical presence of caspase-8, but rather enzymatic activity that is required for the activation of NF-kappaB.