Biomedical Sciences Graduate Program | University of California, San Francisco

Averil Ma, MD, PhD
Ubiquitination, Cell Signaling and Autoimmunity

Selected Publications | Complete Publications

phone	502-9405
email	averil.ma@ucsf.edu
additional websites	lab website Cancer Center
secondary research affiliation	Cancer Biology & Cell Signaling

The proper regulation of innate immunity is critical for preventing autoimmunity. Our laboratory’s interest in this area has focused on the intracellular mechanisms by which innate immune signaling, including TNF and TLR induced signal transduction events are regulated. In particular, by targeting the A20 gene in mice, we have found that a novel molecule called A20 is essential for restricting TNF, TLR and NOD induced activation signals in macrophages and dendritic cells (Lee et al, Science 2000, Boone et al, Nature Immunology 2004; Turer et al, J Exp Med 2008; Hitotsumatsu et al, Immunity 2008). We have further found that A20 is a unique ubiquitin modifying enzyme that requlates both the activity and stability of signaling proteins such as RIP and TRAF6 (Wertz et al, Nature 2004; Boone et al, Nature Immunology 2004). A20 is a biochemically unique molecule that both deactivates and degrades target proteins. A20 appears to work with other ubiquitin dependent proteins, such as ABIN-1, and ABIN-1 deficiency is independently critical for regulating TNF signals (Oshima et al, Nature 2009).

In addition to being biologically and biochemically potent molecules, these proteins are extraordinarily important for human diseases. Recent genetic studies suggest that A20 is important for regulating multiple autoimmune diseases in human patients (e.g., Musone et al, Nature Genetics 2008). In addition, loss of A20 function is pathogenetic in a large percentage of human B cell malignancies. Ongoing studies focus on the mechanisms by which A20, ABIN-1, and related proteins function, on the cell signaling cascades and cellular functions impacted by these proteins, and on the roles of the roles of these ubiquitin dependent proteins in regulating immune responses and autoimmunity.

Selected Publications

Lodolce JP, Boone DL, Dassopoulos T, Chai S, Swain RE, Trettin S, and Ma A. 1998. Interleukin-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9; 669-676.

Lee EG, Boone DL, Libby S, Chai S, Chien M, Lodolce JP, and Ma A . 2000. Failure to regulate TNF induced NF-?B and cell death responses in A20 deficient mice. Science 289 ;2350.

Burkett PR, Koka R, Chien M, Chai S, and Ma A. 2004. Coordinate Expression and Trans Presentation of IL-15Ra and IL-15 Supports NK Cell and Memory CD8 + T Cell Homeostasis. J ExpMed 200;825-834.

Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM. 2004. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430, 694-699.

Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, McNally E, Pickart C, and Ma A. 2004. The ubiquitin modifiying enzyme A20 is essential for terminating TLR signaling. Nature Immunology 5 ;1052-60.

Turer EE, Tavares R, Hitotsumatsu O, Advincula R, Lee BL, Shifrin N, Malynn BA, and Ma A. 2008. Homeostatic MyD88 dependent signals cause lethal inflammation in the absence of A20. J Exp Med 205;451-464.

Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, Lee BL, Shifrin N, Advincula R, Malynn BA, Werts C, and Ma A. 2008. The ubiquitin editing enzyme A20 restricts NOD2 triggered signals. Immunity 28;381-390.

Mortier E, Woo T, Advincula R, Gozalo S, and Ma A. 2008. IL-15Ra chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans-presentation. J Exp Med 205;1213-1225.

Werner SL, Kearns JD, Zadorozhnaya V, Lynch C, O’Dea E, Boldin MP, Ma A, Baltimore D, and Hoffman A. Encoding NFkB temporal control in response to TNF: distinct roles for the negative regulators IkBa and A20. 2008. Genes Dev 22;2093-2101.

Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, Shifrin N, Petri MA, Kamboh MI, Manzi S, Seldin MF, Gregersen PK, Behrens TW, Ma A, Kwok PY and Criswell LA. 2008. Multiple polymorphisms in the TNFAIP3 [A20] region are independently associated with systemic lupus erythematosus. Nat Genetics 40;1062-1064.

Ma A. 2008. Unresolved ER stress inflames the intestine. Cell 134;724-726.

Oshima S, Turer EE, Callahan JA, Advincula R, Chai S, Barrera J, Shifrin N, Lee B, Woo T, Malynn BA, and Ma A. 2009. ABIN-1 is a ubiquitin sensor that restricts TNF induced cell death and sustains embryonic development. Nature 457;906-910.

Malynn BA and Ma A. 2009. A20 takes on tumors: tumor suppression by a ubiquitin editing enzyme. J Exp Med (epub April 20, 2009)

information last updated May 2009