Ubiquitin-dependent regulators of immunity
The Ma Lab's research centers around ubiquitin-dependent regulators of immunity. A number of proteins serve diverse roles in the immune system. After being synthesized, these proteins are often modified by the addition of another protein, known as ubiquitin, in a process known as ubiquitylation. Ubiquitylation can activate and/or deactivate proteins and their associated signaling pathways, leading to cell growth, differentiation, or death (among many other outcomes). Various proteins and enzymes catalyze ubiquitylation in the immune system; the improper function or absence of these proteins are associated with a variety of inflammatory diseases. We study these proteins, their functions, and the pathways they participate in. We also elucidate their role in human autoimmune disease and contribute to novel therapeutics targeting these.
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 of many ubiquitin-dependent regulators of immunity is A20. A20 is a deubiquitinating 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 is generously supported by the National Institutes of Health (NIH), the Crohn's and Colitis Foundation, the Lupus Research Institute, and the Kenneth Rainin Foundation.
