An Allosteric MALT1 Inhibitor Is a Molecular Corrector Rescuing Function in an Immunodeficient Patient
This week we profile a recent publication in Nature Chemical Biology from the laboratories of Dr. Stuart Turvey at the BC
Children’s Hospital and UBC, and Dr. Christopher Overall (pictured left) at the Center for Blood Research and UBC.
Can you provide a brief overview of your lab’s current research focus?
My lab is focused on degradomics, the proteomic study of proteases and their inhibitors, in health and disease. We have developed a suite of proteomics techniques and software to dissect the roles of proteases in cells and tissues, discern the substrate repertoire and thus functions of individual proteases, and to dissect interactions in the protease web. Currently we are applying degradomics to evaluate the role of proteases in various human diseases for deeper mechanistic understanding of pathological mechanisms.
What is the significance of the findings in this publication?
MALT1 is a cysteine protease with both proteolytic and scaffolding functions that are key for the regulation of lymphocyte activation in response to antigen and TNF stimulation. We previously described a patient with combined immunodeficiency resulting from a homozygous W580S-MALT1 mutation that reduced levels of MALT1 (1). Here we show that Trp580 is required for protein stability, mediating interactions between the paracaspase and C-terminal immunoglobulin domains of MALT1. We discovered nanomolar allosteric inhibitors, MLT-748 and MLT-747, that inhibit MALT1 by displacing the side chain of Trp580 that locks the protease in an inactive state. In the patient W580S-MALT1, the inhibitors replace Trp580, stabilise the mutant MALT1 and restore protein levels and signalling functions in NFkB activation. Following washout of the inhibitor, the W580S-MALT1 regained partial cleavage activity. Thus, we describe molecular correctors that rescue a genetic deficiency of MALT1 that function as a molecular prosthetic.
What are the next steps for this research?
The W580S-MALT1 patient was cured by a hematopoietic stem cell transplant. Our inhibitors could be used not only to treat patients with overactive MALT1 that is often observed in B-cell lymphomas, but also to treat patients with mutations in the region of W580 as they await hematopoietic stem cell transplantation. This research highlights the potential for treating other genetic mutations that result in defects in enzyme stability and activity using small molecule pharmacological correctors, in an individualized precision medicine approach.
This work was funded by:
C.M.O. holds a Canada Research Chair in Protease Proteomics and Systems Biology (number: 950-20-3877). This work was supported by Canadian Institutes of Health Research grants (MOP-133691 to S.E.T. and FDN: 148408, MOP-37937 to C.M.O.), Natural Sciences and Engineering Research Council of Canada (RGPIN 435829-201 to S.E.T), the Michael Smith Foundation for Health Research to establish the British Columbia Proteomics Network (IN-NPG-00105-156 to C.M.O.) and the Canada Foundation for Innovation (31059 to C.M.O.).
Ref (1) Klein, T. et al. The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κ B signalling. Nat. Commun. 6, 8777 (2015).