Toll-like receptor 4-mediated c-Jun N-terminal kinase activation induces gp96 cell surface expression via AIMP1 phosphorylation.
The presentation of the endoplasmic reticulum resident chaperone protein, gp96 on the cell surface have been considered as a phenomenon of the immunogenic process activation. Previously, we showed aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) can form a molecular complex with gp96, regulate the ER retention of gp96 through KDEL receptor, and suppress its cell surface expression. However, the physiological conditions that modulate AIMP1-gp96 interaction and cell surface expression of gp96 are not known. In this study, we investigated the process that which can modulate dissociation of AIMP1 and gp96 by using Toll-like receptor (TLR) activation. MyD88 pathway by LPS-mediated TLR4 activation induced the cell surface presentation of gp96 through c-Jun N-terminal kinase (JNK). AIMP1 was phosphorylated by JNK upon LPS stimulation and gp96 was dissociated from phosphorylated AIMP1. We further demonstrated that serine-140 residue of AIMP1 was phosphorylated by JNK and alanine mutation of serine-140 suppressed LPS-induced cell surface expression of gp96. Altogether, these results suggest that AIMP1 is phosphorylated by JNK through TLR-MyD88 pathway and lose the regulatory activity for ER retention of gp96, resulting in the increase of cell surface expression of gp96, and provide a new molecular mechanism underlying TLR-mediated gp96 regulation.
Center for Medicinal Protein Network and Systems Biology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Gyuyoup
G
Kim
Jung Min
JM
Han
Sunghoon
S
Kim
D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D007113:Immunity, Innate; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000276:immunology; D018832:Molecular Chaperones / Q000096:biosynthesis*; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D000951:Antigens, Neoplasm; D016207:Cytokines; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D018832:Molecular Chaperones; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C052646:sarcoma glycoprotein gp96 rejection antigens; C077219:small inducible cytokine subfamily E, member 1; D012694:Serine; D048031:JNK Mitogen-Activated Protein Kinases