Toll-like receptor 4-mediated c-Jun N-terminal kinase activation induces gp96 cell surface expression via AIMP1 phosphorylation

Abstract

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.