Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation: evidence that WIP-WASP dissociation is not required and that the WIP NH2 terminus is inhibitory

Details

Serval ID
serval:BIB_7505FC5E0F72
Type
Article: article from journal or magazin.
Collection
Publications
Title
Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation: evidence that WIP-WASP dissociation is not required and that the WIP NH2 terminus is inhibitory
Journal
J Biol Chem
Author(s)
Dong X., Patino-Lopez G., Candotti F., Shaw S.
ISSN
0021-9258 (Print)
ISSN-L
0021-9258
Publication state
Published
Issued date
2007
Volume
282
Number
41
Pages
30303-10
Language
english
Notes
Dong, Xiaoyun
Patino-Lopez, Genaro
Candotti, Fabio
Shaw, Stephen
eng
Z01 BC009257-31/Intramural NIH HHS/
Z99 CA999999/Intramural NIH HHS/
Research Support, N.I.H., Intramural
J Biol Chem. 2007 Oct 12;282(41):30303-10. Epub 2007 Aug 20.
Abstract
WASP and its binding partner WIP play important roles in T cells both in actin polymerization and in interleukin-2 transcription. Aberrations thereof contribute to the pathology of Wiskott-Aldrich syndrome (WAS). To directly evaluate the cooperativity of WIP and WASP in interleukin-2 transcription, we investigated how the WIP-WASP complex regulates NF-AT-mediated gene transcription. We developed an improved model system for analysis, using WIP and WASP cotransfection into Jurkat cells, in which strong induction of NFAT reporter activation is observed with anti-T cell receptor (TCR) antibody without the phorbol 12-myristate 13-acetate usually used previously. Using this system, our findings contradict a prevailing conceptual model of TCR-induced WIP-WASP dissociation by showing in three ways that the WIP-WASP complex mediates TCR-induced NFAT activation without dissociation. First, phosphorylation of WIP Ser(488) does not cause dissociation of the WIP-WASP complex. Second, WIP-WASP complexes do not dissociate demonstrably after TCR stimulation. Third, a fusion protein of WIP to WASP efficiently mediates NFAT activation. Next, our studies clarify that WIP stabilization of WASP explains otherwise unexpected results in TCR-induced NFAT activation. Finally, we find that the NH(2) terminus of WIP is a highly inhibitory region for TCR-mediated transcriptional activation in which at least two elements contribute: the NH(2)-terminal polyproline and the NH(2)-terminal actin-binding WH2 domain. This suggests that WIP, like WASP, is subject to autoinhibition. Our data indicate that the WIP-WASP complex plays an important role in WASP stabilization and NFAT activation.
Keywords
Actins/chemistry, Antigens, CD3/biosynthesis, Cytoskeletal Proteins/*metabolism, Humans, Interleukin-2/metabolism, Intracellular Signaling Peptides and Proteins/*metabolism, Jurkat Cells, Kinetics, Models, Biological, NFATC Transcription Factors/chemistry/*physiology, Protein Structure, Tertiary, Receptors, Antigen, T-Cell/metabolism, Structure-Activity Relationship, Tetradecanoylphorbol Acetate/chemistry, *Transcription, Genetic, Wiskott-Aldrich Syndrome/metabolism, Wiskott-Aldrich Syndrome Protein/*metabolism
Pubmed
Open Access
Yes
Create date
01/11/2017 11:29
Last modification date
20/08/2019 15:32
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