Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator.
The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.
Voong
Lilien N
LN
Department of Biology, Sarah Lawrence College, 1 Mead Way, Bronxville, NY 10708, USA.
Slater
Allison R
AR
Kratovac
Sebila
S
Cressman
Drew E
DE
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation / Q000502:physiology; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002522:Chlorocebus aethiops; D019281:Dimerization; D006160:Guanosine Triphosphate / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D000097606:Exportin 1 Protein
D006160:Guanosine Triphosphate; D000949:Histocompatibility Antigens Class II; D028884:Karyopherins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D000097606:Exportin 1 Protein; C083728:MHC class II transactivator protein