Targeting MALT1 Proteolytic Activity in Immunity, Inflammation and Disease: Good or Bad?

MALT1 is a signaling protein that plays a key role in immunity, inflammation, and lymphoid malignancies. For a long time MALT1 was believed to function as a scaffold protein, providing an assembly platform for other signaling proteins. This view changed dramatically when MALT1 was also found to have proteolytic activity and a capacity to fine-tune immune responses. Preclinical studies have fostered the belief that MALT1 is a promising therapeutic target in autoimmunity and B cell lymphomas. However, recent studies have shown that mice expressing catalytically-inactive MALT1 develop multi-organ inflammation and autoimmunity, and thus have tempered this initial enthusiasm. We discuss recent findings, highlighting the urgent need for a better mechanistic and functional understanding of MALT1 in host defense and disease.

TrendsThe original finding that MALT1 holds proteolytic activity has caused a conceptual breakthrough in antigen receptor signaling.The description of novel receptors signaling via MALT1 and the identification of novel MALT1 substrates ascribes new biological functions to this protein.Preclinical studies with MALT1-deficient mice or small compound inhibitors foster the belief that MALT1 is a promising therapeutic target in autoimmune diseases and B cell lymphoma subtypes.Four recent studies showing that protease-dead MALT1 knock-in mice develop an inflammatory phenotype have somewhat tempered the initial enthusiasm of MALT1 as a potential therapeutic target.Germline mutations affecting MALT1 in patients are emerging as the cause of novel combined immunodeficiency phenotypes.