CMIP is a negative regulator of T cell signaling.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
CD28 Antigens
/ metabolism
CD3 Complex
/ metabolism
Cell Polarity
Cytokines
/ metabolism
Enzyme Activation
Glycosphingolipids
/ metabolism
Humans
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
/ metabolism
Membrane Microdomains
/ metabolism
Mice, Transgenic
Phenotype
Proteomics
Proto-Oncogene Proteins c-fyn
/ metabolism
Signal Transduction
T-Lymphocytes
/ metabolism
src-Family Kinases
/ metabolism
CMIP
T cells
Transgenic mice
Journal
Cellular & molecular immunology
ISSN: 2042-0226
Titre abrégé: Cell Mol Immunol
Pays: China
ID NLM: 101242872
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
01
12
2018
accepted:
10
07
2019
pubmed:
10
8
2019
medline:
1
10
2021
entrez:
10
8
2019
Statut:
ppublish
Résumé
Upon their interaction with cognate antigen, T cells integrate different extracellular and intracellular signals involving basal and induced protein-protein interactions, as well as the binding of proteins to lipids, which can lead to either cell activation or inhibition. Here, we show that the selective T cell expression of CMIP, a new adapter protein, by targeted transgenesis drives T cells toward a naïve phenotype. We found that CMIP inhibits activation of the Src kinases Fyn and Lck after CD3/CD28 costimulation and the subsequent localization of Fyn and Lck to LRs. Video microscopy analysis showed that CMIP blocks the recruitment of LAT and the lipid raft marker cholera toxin B at the site of TCR engagement. Proteomic analysis identified several protein clusters differentially modulated by CMIP and, notably, Cofilin-1, which is inactivated in CMIP-expressing T cells. Moreover, transgenic T cells exhibited the downregulation of GM3 synthase, a key enzyme involved in the biosynthesis of gangliosides. These results suggest that CMIP negatively impacts proximal signaling and cytoskeletal rearrangement and defines a new mechanism for the negative regulation of T cells that could be a therapeutic target.
Identifiants
pubmed: 31395948
doi: 10.1038/s41423-019-0266-5
pii: 10.1038/s41423-019-0266-5
pmc: PMC7609264
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CD28 Antigens
0
CD3 Complex
0
CMIP protein, human
0
Cmip protein, mouse
0
Cytokines
0
Glycosphingolipids
0
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
EC 2.7.10.2
Proto-Oncogene Proteins c-fyn
EC 2.7.10.2
src-Family Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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