Aminoacyl-tRNA Synthetase-Interacting Multifunctional Protein 1/p43 Controls Endoplasmic Reticulum Retention of Heat Shock Protein gp96

• DOI: 10.2353/ajpath.2007.061266
• Publication Date: 2007-04-13T19:34:05Z
• Authors: Jung Min Han; Sang Gyu Park; Bei Liu; Bum-Joon Park; Jin Young Kim; Cheng He Jin; Yeong Wook Song; Zihai Li; Sunghoon Kim
• Keywords: Mice, Knockout; 0301 basic medicine; Membrane Glycoproteins; Receptors, Peptide; Recombinant Fusion Proteins; Endoplasmic Reticulum; Autoimmune Diseases; Mice; 03 medical and health sciences; Phenotype; Animals; Cytokines; Lupus Erythematosus, Systemic; Dimerization; Cells, Cultured; Heat-Shock Proteins; Spleen

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1; previously known as p43) is a multifunctional protein that was initially found in multitRNA synthetase complex. In the present study, screening of the AIMP1-binding proteins revealed that AIMP1 can form a molecular complex with heat shock protein gp96. AIMP1 enhances gp96 dimerization and the interaction between gp96 and KDEL receptor-1 (KDELR-1), which mediates the retrieval of KDEL-containing proteins from Golgi to the endoplasmic reticulum (ER). The interaction between gp96 and KDELR-1 was reduced in AIMP1-deficient cells, and this disturbed ER retention of gp96 and increased its cell surface localization. Moreover, this localization of gp96 at the cell surface was suppressed by its interaction with AIMP1 and enhanced by the depletion of endogenous AIMP1. In addition, AIMP1-deficient mice showed dendritic cell activation attributable to increased gp96 surface presentation and lupus-like autoimmune phenotypes. These results suggest that AIMP1 acts as a regulator of the ER retention of gp96 and provide a new perspective of the regulatory mechanism underlying immune stimulation by gp96.