[PDF][PDF] The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity

RM Tavares, EE Turer, CL Liu, R Advincula, P Scapini… - Immunity, 2010 - cell.com
RM Tavares, EE Turer, CL Liu, R Advincula, P Scapini, L Rhee, J Barrera, CA Lowell, PJ Utz…
Immunity, 2010cell.com
A20 is a ubiquitin modifying enzyme that restricts NF-κB 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-κB responses to CD40-induced signals. Mice expressing absent or …
Summary
A20 is a ubiquitin modifying enzyme that restricts NF-κB 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-κB 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-κB-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.
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