Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN

• Published in: EMBO reports Vol. 7; no. 10; pp. 1023 - 1029
• Main Authors: Löwenberg, Mark, Verhaar, Auke P, Bilderbeek, Joyce, van Marle, Jan, Buttgereit, Frank, Peppelenbosch, Maikel P, van Deventer, Sander J, Hommes, Daniel W
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-10-2006; Blackwell Publishing Ltd
• Subjects: CD4 Antigens - metabolism; Cells, Cultured; Dexamethasone - pharmacology; glucocorticoid receptor; glucocorticoids; Glucocorticoids - pharmacology; Hormones; HSP90 Heat-Shock Proteins - metabolism; Humans; Leukocytes - metabolism; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; Lymphocytes; Models, Biological; Molecular biology; Multiprotein Complexes - drug effects; nongenomic; Protein Binding; Proteins; Proto-Oncogene Proteins c-fyn - metabolism; Receptors, Antigen, T-Cell - metabolism; Receptors, Glucocorticoid - metabolism; RNA Interference - physiology; RNA, Small Interfering - pharmacology; Scientific Report; Signal transduction; T cell; T cell receptors; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tissue Distribution; Transfection
• ISSN: 1469-221X; 1469-3178; 1469-221X
• DOI: 10.1038/sj.embor.7400775

Although glucocorticoid (GC)‐induced nongenomic effects have been reported, the underlying mechanisms remain unexplained. We previously described that lymphocyte‐specific protein tyrosine kinase (LCK) and FYN oncogene related to SRC, FGR, YES (FYN) mediate GC‐induced inhibition of T‐cell‐receptor (TCR) signalling. Here we characterize the underlying molecular mechanism. The present study shows that the GC receptor is part of a TCR‐linked multiprotein complex containing heat‐shock protein (HSP)90, LCK and FYN, which is essential for TCR‐dependent LCK/FYN activation. Experiments with cells transfected with GC‐receptor short interfering RNA (siRNA) showed that the GC receptor is an essential component of the TCR signalling complex. Short‐term GC treatment induces dissociation of this protein complex, resulting in impaired TCR signalling as a consequence of abrogated LCK/FYN activation. HSP90siRNA‐transfected cells are not able to assemble this TCR‐associated multiprotein complex, and accordingly HSP90siRNA treatment mimics GC effects on LCK/FYN activities. These observations support a model for nongenomic GC‐induced immunosuppression on the basis of dissolution of membrane‐bound GC‐receptor multiprotein complexes after GC‐receptor ligation.