Abstract
The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.
Highlights
The paracaspase MALT1 is a proteolytic enzyme whose function is essential for adaptive immune responses and the development of particular lymphocyte subsets, such as Treg cells, marginal zone, and B1 B cells [1,2,3,4,5,6]
These findings identify the Ig3 domain of MALT1 as a novel ubiquitin-binding domain and provide insight into the molecular requirements for MALT1 activation that could be of therapeutic interest
We identify the Ig3 domain of MALT1 as a novel ubiquitin-binding motif that is essential for MALT1 activation through an allosteric mechanism
Summary
The paracaspase MALT1 is a proteolytic enzyme whose function is essential for adaptive immune responses and the development of particular lymphocyte subsets, such as Treg cells, marginal zone, and B1 B cells [1,2,3,4,5,6]. MALT1 contains an N-terminal death domain (DD) that binds to the core of the BCL10 filament by interacting with the BCL10 CARD motif [9]. The C-terminal part of MALT1 that comprises the protease domain is thought to protrude from the filamentous core [9], but the exact conformation and activation status of MALT1 within the BCL10/MALT1 fibers remain unknown. We demonstrated an interaction of ubiquitin with an unknown binding site within the C-terminal half of MALT1, which comprises the protease domain, the Ig3 domain, and a nonstructured C-terminal extension [15]. We present experimental evidence that suggests that ubiquitin binding to the Ig3 domain is required for MALT1 monoubiquitination, which, in turn, perturbs an inhibitory interaction of the Ig3 domain with the protease domain and induces conformational changes within the catalytic domain that lead to enhanced activity
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