AKT/SGK-sensitive phosphorylation of GSK3 in the regulation of L-selectin and perforin expression as well as activation induced cell death of T-lymphocytes.
Survival and function of T-lymphocytes critically depends on phosphoinositide (PI) 3 kinase. PI3 kinase signaling includes the PKB/Akt and SGK dependent phosphorylation and thus inhibition of glycogen synthase kinase GSK3α,β. Lithium, a known unspecific GSK3 inhibitor protects against experimental autoimmune encephalomyelitis. The present study explored, whether Akt/SGK-dependent regulation of GSK3 activity is a determinant of T cell survival and function. Experiments were performed in mutant mice in which Akt/SGK-dependent GSK3α,β inhibition was disrupted by replacement of the serine residue in the respective SGK/Akt-phosphorylation consensus sequence by alanine (gsk3(KI)). T cells from gsk3(KI) mice were compared to T cells from corresponding wild type mice (gsk3(WT)). As a result, in gsk3(KI) CD4(+) cells surface CD62L (L-selectin) was significantly less abundant than in gsk3(WT) CD4(+) cells. Upon activation in vitro T cells from gsk3(KI) mice reacted with enhanced perforin production and reduced activation induced cell death. Cytokine production was rather reduced in gsk3(KI) T cells, suggesting that GSK3 induces effector function in CD8(+) T cells. In conclusion, PKB/Akt and SGK sensitive phosphorylation of GSK3α,β is a potent regulator of perforin expression and activation induced cell death in T lymphocytes.
Department of Physiology, University of Tübingen, Germany.
Shefalee K
SK
Bhavsar
Katja
K
Merches
Diwakar
D
Bobbala
Florian
F
Lang
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015551:Autoimmunity; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins / Q000378:metabolism*; D019041:L-Selectin / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D054353:Perforin / Q000096:biosynthesis*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D019041:L-Selectin; D054353:Perforin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099184:Serum-Glucocorticoid Regulated Kinases; C448021:glycogen synthase kinase 3 alpha