The proper regulation of cell signaling is critical for preventing autoimmune, inflammatory and malignant diseases. Our laboratory has focused recently on understanding how ubiquitination, ubiquitin binding proteins, and ubiquitin modifying enzymes regulate immune cell signaling. We have found that A20 is a potent anti-inflammatory protein that is genetically linked to multiple human diseases, including rheumatoid arthritis, systemic lupus erythematosus, psoriasis, celiac disease, inflammatory bowel diseases, diabetes, atherosclerosis, lymphoma and colon cancer. A20 restricts multiple NFkB and cell death signals. We have further found that A20 is a biochemically unique molecule that utilizes de-ubiquitinating, E3 ligase, and ubiquitin binding motifs to regulate the activity and stability of signaling proteins such as RIP, TRAF6, and IKKg. A20 appears to work with other ubiquitin dependent proteins, such as ABIN-1, which are also genetically linked to human diseases. Ongoing studies focus on the cell-specific functions of these pleiotropically expressed proteins, the mechanisms by which A20, ABIN-1, and related proteins regulate signaling cascades, and the roles of these ubiquitin dependent signals in regulating immune responses.
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.
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.
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.
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.
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.
Shembade N, Ma A, and Harhaj E. 2010. Inhibition of NFkB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327;1135-39.
Tavares RM, Turer EE, Liu C-L, Advincula R, Scapini P, Rhee L, Barrera J, Lowell CA, Utz PJ, Malynn BA, and Ma A. 2010. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity 33;181-191.
Skaug B, Chen J, Du F, He J, Ma A, and Chen ZJ. 2011. Direct, noncatalytic mechanism of IKK inhibition by A20. Molecular Cell 44;1-13.
Hammer GE, Turer EE, Taylor KE, Fang CJ, Advincula R, Oshima S, Barrera J, Huang EJ, Hou B, Malynn BA, Reizis B, Franco A, Criswell LA, Nakamura MC, and Ma A. 2011. Dendritic cell expression of A20 preserves immune homeostasis and prevents colitis and spondyloarthritis. Nature Immunology 12;1184-93.
Tokunaga F, Nishimasu H, Ishitani R, Goto E, Noguchi T, Mio K, Kamei K, Ma A, Iwai K, and Nureki O. 2012. Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kB regulation. EMBO J 31;3856-70.
Shao L, Oshima S, Duong B, Advincula R, Barrera J, Malynn BA, and Ma A. 2013. A20 restricts Wnt signaling in intestinal epithelial cells and suppresses colon tumorigenesis. PLoS One 8;(5):e62223.
Lu TT, Onizawa M, Hammer G, Turer EE, Yin Q, Damko E, Shifrin N, Advincula R, Barrera J, Malynn BA, Wu H, and Ma A. 2013. Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme. Immunity 38;896-905.
CallahanJA, HammerGE, AgelidesA, DuongBH, OshimaS, NorthJ, AdvinculaR, ShifrinN, TruongH, PawJ, BarreraJ, DeFrancoA, RosenblumMD, MalynnBA, and MaA. 2013. ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells. JI (Cutting Edge) 191;535-9.
Duong BH, Onizawa M, Oses-Prieto JA, Advincula R, Burlingame A, Malynn BA, and Ma A. 2015. A20 restricts ubiquitination of pro-IL-1β protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42;55-67.
Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang M, Advincula R, Agelidis A, Barrera J, Burlingame A, Wu H, Malynn BA, Zamvil SS, and Ma A. 2015. A20 restricts RIP3 ubiquitination and protects cells from necroptosis. Nature Immunology 16;618-27.