Toll like receptors (TLRs) on eukaryotic cells mediate the recognition of microbial molecules and regulate host responses to microbial pathogens. Proper regulation of TLR signals not only restricts the intensity and duration of inflammatory responses, but may also maintain immune homeostasis in the intestine, where a plethora of microbial pathogens co-exist with host cells. Recent studies from our labs indicate that A20 is a novel protein that is required for terminating TLR induced signals on myeloid cells and for preventing excessive inflammatory responses in vivo. Our preliminary data suggest that A20 is essential for restricting TLR signals in vivo. Moreover, our findings suggest that A20 may be a novel enzyme that performs this critical function by directly modulating the ubiquitylation status of TLR signaling proteins such as TRAF6. These modifications may cause both de-activation and degradation of TLR signaling proteins. These exciting preliminary findings provide us with unique opportunities to test our central hypothesis that A20 regulates ubiquitylation of signaling proteins, TLR signals, and immune homeostasis. This application represents a synergistic effort between the genetic and cellular expertises of the Ma lab and the biochemical expertise of the Pickart lab to determine: (i) whether A20 is essential for regulating TLR responses in mice;(ii) whether A20 regulates ubiquitylation of critical TLR signaling proteins;and (iii) how A20 recognizes ubiquitylated proteins and may function as both a de-ubiquitylating enzyme and an E3. Results from these studies promise to yield significant insights into how A20 links the regulation of ubiquitylation with disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
Zip Code
Onizawa, Michio; Oshima, Shigeru; Schulze-Topphoff, Ulf et al. (2015) Erratum: The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16:785
Ma, Averil (2015) From trash collectors to guardians of cell signaling and immune homeostasis. Immunol Rev 266:1-5
Duong, Bao H; Onizawa, Michio; Oses-Prieto, Juan A et al. (2015) A20 restricts ubiquitination of pro-interleukin-1? protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42:55-67
Onizawa, Michio; Oshima, Shigeru; Schulze-Topphoff, Ulf et al. (2015) The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16:618-27
Hammer, Gianna Elena; Ma, Averil (2013) Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol 31:743-91
Lu, Timothy T; Onizawa, Michio; Hammer, Gianna E et al. (2013) Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme. Immunity 38:896-905
Ma, Averil; Malynn, Barbara A (2012) A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12:774-85
Hammer, Gianna Elena; Turer, Emre E; Taylor, Kimberly E et al. (2011) Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 12:1184-93
Ashida, Hiroshi; Kim, Minsoo; Schmidt-Supprian, Marc et al. (2010) A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat Cell Biol 12:66-73; sup pp 1-9
Malynn, Barbara A; Ma, Averil (2010) Ubiquitin makes its mark on immune regulation. Immunity 33:843-52

Showing the most recent 10 out of 15 publications