Increased Protein Stability and Interleukin-2 Production of a LATG131D Variant With Possible Implications for T Cell Anergy
Mikel M. Arbulo-Echevarria , Inmaculada Vico-Barranco , Isaac Narbona-Sánchez , Francisco García-Cózar , Arkadiusz Miążek , Enrique Aguado
AbstractThe adaptor LAT plays a crucial role in the transduction of signals coming from the TCR/CD3 complex. Phosphorylation of some of its tyrosines generates recruitment sites for other cytosolic signaling molecules. Tyrosine 132 in human LAT is essential for PLC-γ activation and calcium influx generation. It has been recently reported that a conserved glycine residue preceding tyrosine 132 decreases its phosphorylation kinetics, which constitutes a mechanism for ligand discrimination. Here we confirm that a LAT mutant in which glycine 131 has been substituted by an aspartate (LATG131D) increases phosphorylation of Tyr132, PLC-γ activation and calcium influx generation. Interestingly, the LATG131D mutant has a slower protein turnover while being equally sensitive to Fas- mediated protein cleavage by caspases. Moreover, J.CaM2 cells expressing LATG131D secrete greater amounts of interleukin-2 (IL-2) in response to CD3/CD28 engagement. However, despite this increased IL-2 secretion, J.CaM2 cells expressing the LATG131D mutant are more sensitive to inhibition of IL-2 production by pre-treatment with anti- CD3, which points to a possible role of this residue in the generation of anergy. Our results suggest that the increased kinetics of LAT Tyr132 phosphorylation could contribute to the establishment of T cell anergy, and thus constitutes an earliest known intracellular event responsible for the induction of peripheral tolerance.
|Journal series||Frontiers in Cell and Developmental Biology, ISSN , e-ISSN 2296-634X, (N/A 70 pkt)|
|Publication size in sheets||0.5|
|Keywords in English||LAT, TCR, phosphorylation, anergy, IL-2 (interleukin-2)|
|License||Journal (articles only); published final; ; with publication|
|Score||= 70.0, 10-03-2021, ArticleFromJournal|
|Publication indicators||= 0; = 0; : 2019 = 5.201 (2)|
|Citation count*||2 (2021-05-09)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.