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Drosophila sensory neurons tile the larval body wall, Dr. Chun Han

Faculty

Office: 
Campus Address: S1057 Box: 0451
Phone: 
(415) 502-9405

Averil Ma

Ubiquitination and cell signaling

Our laboratory studies factors that regulate immune homeostasis.  We discovered the critical role of A20 in maintaining immune homeostasis by generating and characterizing A20 deficient mice (Lee et al, Science). We found that homeostatic Myd88 dependent signals drive a major portion of A20 restricted pro-inflammatory signals (Turer et al, J Exp Med).  We utilized genetic epistasis and signaling approaches to unveil A20’s functions in restricting TNF, TLR and NOD2 triggered NFkB signals (Lee et al, Science; Boone et al, Nature Immunology; Hitotsumatsu et al, Immunity).  We found that A20 is a de-ubiquitinating enzyme (Boone et al, Nature Immunology) that also exhibits E3 ligase activity (Wertz et al, Nature).  In addition, non-catalytic mechanisms may contribute to A20’s biochemical functions (Skaug et al, Mol Cell).  We are thus studying the mechanisms by which A20 restricts specific ubiquitin dependent signaling cascades.

One important component of A20-mediated regulation of signaling may be ABIN-1, a protein that binds to A20.  By generating ABIN-1 deficient mice, we discovered that ABIN-1, like A20, restricts TNF induced cell death and preserves embryonic survival (Oshima et al, Nature).  While A20 is a ubiquitin editing enzyme, ABIN-1 is a ubiquitin sensor with no known enzymatic activity.  We and others have linked both A20 and ABIN-1 to human rheumatoid arthritis, SLE, psoriasis, sprue and IBD (Musone et al, Nature Genetics).  We have generated mice lacking A20 in selected lineages and shown that A20 deficiency in B cells causes SLE-like disease (Tavares et al, Immunity).  By contrast, mice lacking A20 in dendritic cells develop colitis and sero-negative arthritis (Hammer et al, Nature Immunology).  We are using these mice and cells to investigate the links between ubiquitin dependent intracellular signaling and inflammatory/autoimmune diseases.