MALT1 alternative splicing—A molecular rheostat for balancing immune activation and homeostasis

MALT1 (mucosa-associated lymphoid tissue lymphoma/leukemia protein 1)–TRAF6 [tumor necrosis factor receptor (TNFR)-associated factor 6] interaction drives lymphocyte activation and adaptive immunity, but it also contributes to maintaining immune homeostasis. MALT1 exists in two isoforms that differ only by either encoding two (MALT1A) or one (MALT1B) TRAF6 binding motif (T6BM). The human mutation MALT1 E806D in T6BM2, expressed in both MALT1A and MALT1B, has been associated with an immune disorder combining symptoms of immune deficiency and autoimmunity. Here, we report that the orthologous germline mutation MALT1 E814D is sufficient to induce a fatal autoimmune syndrome in mice. We demonstrate that species-specific differences in the effects of T6BM2 disruptions can be attributed to alterations in MALT1 splicing and that immune homeostasis is restored by genetically enforcing expression of MALT1A in MALT1 E814D mice. Thus, alternative MALT1 splicing allows tuning of TRAF6 association, thereby functioning as a molecular rheostat to balance between optimal immune activation and maintenance of peripheral tolerance.