Malt1-dependent RelB cleavage promotes canonical NF-κB activation in lymphocytes and lymphoma cell lines

The protease activity of the paracaspase Malt1 contributes to antigen receptor-mediated lymphocyte activation and lymphomagenesis. Malt1 activity is required for optimal NF-kappa B activation, but little is known about the responsible substrate(s). Here we report that Malt1 cleaved the NF-kappa B family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA-or c-Rel-containing NF-kappa B complexes. Overexpression of RelB inhibited expression of canonical NF-kappa B target genes and led to impaired survival of diffuse large B-cell lymphoma cell lines characterized by constitutive Malt1 activity. These findings identify a central role for Malt1-dependent RelB cleavage in canonical NF-kappa B activation and thereby provide a rationale for the targeting of Malt1 in immunomodulation and cancer treatment.