The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity.
A20 is a ubiquitin modifying enzyme that restricts NF-kappaB signals and protects cells against tumor necrosis factor (TNF)-induced programmed cell death. Given recent data linking A20 (TNFAIP3) with human B cell lymphomas and systemic lupus erythematosus (SLE), we have generated mice bearing a floxed allele of Tnfaip3 to interrogate A20's roles in regulating B cell functions. A20-deficient B cells are hyperresponsive to multiple stimuli and display exaggerated NF-kappaB responses to CD40-induced signals. Mice expressing absent or hypomorphic amounts of A20 in B cells possess elevated numbers of germinal center B cells, autoantibodies, and glomerular immunoglobulin deposits. A20-deficient B cells are resistant to Fas-mediated cell death, probably due to increased expression of NF-kappaB-dependent antiapoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, whereas A20 protects other cells from TNF-induced cell death. Our studies demonstrate how reduced A20 expression predisposes to autoimmunity.
Tavares
Rita M
RM
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Turer
Emre E
EE
Liu
Chih L
CL
Advincula
Rommel
R
Scapini
Patrizia
P
Rhee
Lesley
L
Barrera
Julio
J
Lowell
Clifford A
CA
Utz
Paul J
PJ
Malynn
Barbara A
BA
Ma
Averil
A
D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D019070:Cell Lineage; D002470:Cell Survival; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D019013:CD40 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse