Title: A novel Zap70 mutation with reduced protein stability demonstrates the rate-limiting threshold for Zap70 in T cell receptor signalling
Authors: Cauwe, Bénédicte *
Tian, Lei *
Franckaert, Dean
Pierson, Wim
Staats, Kim
Schlenner, Susan
Liston, Adrian # ×
Issue Date: Mar-2014
Publisher: Blackwell Scientific Publications
Series Title: Immunology vol:141 issue:3 pages:377-87
Article number: 10.1111/imm.12199
Abstract: Loss of ζ-associated protein 70 (Zap70) results in severe immunodeficiency in humans and mice due to the critical role of Zap70 in TCR signalling. Here we describe a novel mouse strain generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, with the reduced protein stability (rps) mutation in Zap70. The A243V rps mutation resulted in decreased Zap70 protein and a reduced duration of TCR-induced calcium responses, equivalent to that induced by a 50% decrease in catalytically-active Zap70. The reduction of signalling through Zap70 was insufficient to substantially perturb thymic differentiation of conventional CD4 and CD8 T cells, although Foxp3(+) regulatory T cells demonstrated altered thymic production and peripheral homeostasis. Despite the mild phenotype, the Zap70(A243V) variant lies just above the functional threshold for TCR signalling competence, as T cells relying on only a single copy of the Zap70(rps) allele for TCR signalling demonstrated no intracellular calcium response to TCR stimulation. This addition to the Zap70 allelic series indicates that a rate-limiting threshold for Zap70 protein levels exists at which signalling capacity switches from nearly intact to effectively null. This article is protected by copyright. All rights reserved.
ISSN: 0019-2805
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Genetics of Autoimmunity (VIB-KU Leuven Center for Brain & Disease Research)
* (joint) first author
× corresponding author
# (joint) last author

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