Paracaspase MALT1 Deficiency Protects Mice from Autoimmune-Mediated Demyelination

Abstract

The paracaspase MALT 1 is a major player in lymphocyte activation and proliferation. MALT1 mediates Ag-induced signaling to the transcription factor NF-κB by functioning both as a scaffold protein and cysteine protease. We studied the role of MALT1 in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. MALT1-knockout mice did not develop any clinical symptoms of EAE. In addition, lymphocyte and macrophage infiltration into the spinal cord was absent in MALT1-knockout mice, as were demyelination and proinflammatory gene expression. Adoptive transfer experiments showed that MALT1 deficiency in splenocytes is sufficient for EAE resistance. Moreover, autoreactive T cell activation was severely impaired in MALT1-deficient T cells, suggesting the inability of MALT1-deficient effector T cells to induce demyelinating inflammation in the CNS. Finally, the MALT1 substrates A20 and CYLD were completely processed in wild-type T cells during EAE, which was partially impaired in MALT1-deficient T cells, suggesting a contribution of MALT1 proteolytic activity in T cell activation and EAE development. Together, our data indicate that MALT1 may be an interesting therapeutic target in the treatment of multiple sclerosis.

Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

“…MALT1-deficient mice show impaired B- and T-cell responses together with defects in the development of particular lymphocyte subsets such as marginal zone (MZ) and B1 B cells (63, 78). Moreover, these mice are resistant to experimental induction of experimental autoimmune encephalitis, a mouse model of multiple sclerosis (79, 80). Mice expressing a catalytically inactive mutant of MALT1 [C472A knock-in mice, subsequently called MALT1-protease inactive (PI) mice] recapitulate these aspects of the immunodeficiency phenotype of the MALT1 knockout mice to a large extent.…”

Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation

“…While the intact CBM complex is required for canonical NF-κB signaling induced by the antigen receptor 17 , its catalytic activity cleaves targets such as Bcl-10, the deubiquitinases A20 and CYLD and the NF-κB subunit RelB and may thereby modulate canonical and alternative NF-κB signaling 15,16,18,19 as well as signaling by the kinase Jnk 20 . Notably, the presence of MALT1 in dendritic cells and CD4 + T cells seems to be critical for differentiation into the T H 17 subset of helper T cells, and Malt1-deficient mice are resistant to experimentally induced autoimmune encephalomyelitis (EAE) [21][22][23] . Consistent with a requirement for the enzymatic activity of MALT1, pharmacological inhibition of this paracaspase has been shown to attenuate the development of EAE 24 .…”

The role of the ubiquitin-editing enzyme A20 in diseases of the central nervous system and other pathological processes

“…Finally, studies exploring the function of A20 in NF-κB regulation upon MCAO have different conclusions, one stating reduced infarct volume and improvement of neurological deficits in A20 gene deficient rats, though whether these effects were due to reduced NF-κB activity was not examined (Yu et al, 2006). However, another work employing knockout mice for A20, either in the CNS or specifically in neurons, did not detect differences in infarct volume when assessed 24 h after MCAO, although MCAO upregulated A20 expression in wild type mice (Mc Guire et al, 2013). …”

“…In lymphocytes, ubiquitination of MALT-1 by TRAF-6 is a prerequisite for NF-κB activation (Oeckinghaus et al, 2007). The fact that MALT-1 ubiquitination by TRAF6 is essential for TCR- and BCR-induced activation of NF-κB and evidence that MALT-1 plays an important role in the pathogenesis of several autoimmune diseases (e.g., Multiple Sclerosis; Brüstle et al, 2012; Mc Guire et al, 2013) and lymphomas (e.g., Marginal B zone lymphoma and ABC-DLBCL; Ngo et al, 2006; Vega et al, 2011) suggest that MALT-1 inhibition by A20 plays an important role in the prevention of autoimmunity and lymphomas (Figure 2). …”