Ubiquitin-dependent regulators of immunity
The Ma Lab's research centers around ubiquitin-dependent regulators of immunity. Ubiquitylation rapidly modifies proteins, dictating their protein-protein interactions, and plays major roles in regulating cellular signals that drive dynamic cellular processes including cellular activation, differentiation, or death. Importantly, ubiquitin dependent proteins are highly regulated, and improper function or expression of these proteins cause multiple inflammatory diseases in mice and in human patients. We use mass spectrometry, cell signaling, murine genetic engineering, and CRISPR screens to study these proteins, how they regulate immunity, and how they prevent disease. Emerging molecular insights of these proteins are leading toward novel therapeutic approaches targeting disease.
Enzymatic and non-catalytic functions
By genetically engineering a series of mice, we have identified the physiological functions of a number of ubiquitin-dependent proteins implicated in human disease. Our studies of these mice have unveiled several pathways by which these proteins regulate intracellular activation and survival signals, including antigen receptors, toll-like receptors, and tumor necrosis factor (TNF) family receptors. Deficiencies of these proteins cause aberrant lymphoid or myeloid cell activation, inflammasome activation and inflammatory cell death. These defects drive inflammatory diseases.
One prominent regulator of immunity is A20, a ubiquitin modifying enzyme that inhibits activation of the transcription factor NF-κB and restricts apoptosis induced by tumor-necrosis factor. A20 is a potent anti-inflammatory protein linked to multiple human autoimmune diseases and to human malignancies. Polymorphisms in the human TNFAIP3 gene (which encodes the A20 protein) are associated with reduced function or expression of A20 that confers susceptibility to autoimmune diseases. Deletion of A20 in mice leads to widespread tissue inflammation and perinatal death. A20 regulates multiple signaling cascades and has distinct physiological functions in different cell types, including (but not limited to) myeloid cells, T cells, and B cells.
Applications to human health
Our work on ubiquitin-dependent regulators of immunity has been applied to a number of human diseases, including psoriasis and psoriatic arthritis, rheumatoid arthritis, colitis and other inflammatory bowel diseases, lupus, other autoimmune diseases, and various cancers.
A20, or TNFAIP3, is a remarkably potent regulator of Ub dependent signals and of immune homeostasis. Among ubiquitination regulators, A20 has garnered increasing attention because of its multiple links to human disease. Initially, genome wide association studies (GWAS) linked single nucleotide polymorphisms (SNPs) in the A20 gene locus with the incidence of rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis, rheumatoid arthritis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, scleroderma, and asthma. Among disease associated susceptibility SNPs, putative causal SNPs were shown to cause reduced A20 expression. More recently, it was shown that transgenic mice bearing human A20 genes with susceptibility SNPs develop autoimmunity and arthritis. In addition, reductions in A20 expression have been observed independently of germline polymorphisms in both involved and uninvolved tissues from psoriasis and asthma patients. Reduced A20 expression has also been correlated with disease and anti-TNF responsiveness in inflammatory bowel disease patients.
Many of our recent articles chart the course for novel treatments against human disease. Our manuscript "Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis–like disease and inflammation" identified that mutations in the Zinc Finger 7 (ZF7) motif of A20 led to T-cell dependent digit arthritis in mice, resembling the human inflammatory disease psoriatic arthritis. Another of our manuscripts, "Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis", showed that a lack of A20 in dendritic cells led to colitis and other inflammatory bowel disease analogs in mice. These establish A20 as a prominent target for next-generation therapeutics fighting autoimmune diseases.
Support for our research
Our lab's work has been generously supported by the National Institutes of Health (NIH), the Crohn's and Colitis Foundation, and the Kenneth Rainin Foundation.
