title: Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4A.
abstract: The signaling lipid molecule 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) has multiple cellular functions, including anti-inflammatory and antineoplastic activities. Here, we report that 15d-PGJ2 blocks translation through inactivation of translational initiation factor eIF4A. Binding of 15d-PGJ2 to eIF4A blocks the interaction between eIF4A and eIF4G that is essential for translation of many mRNAs. Cysteine 264 in eIF4A is the target site of 15d-PGJ2. The antineoplastic activity of 15d-PGJ2 is likely attributed to inhibition of translation. Moreover, inhibition of translation by 15d-PGJ2 results in stress granule (SG) formation, into which TRAF2 is sequestered. The sequestration of TRAF2 contributes to the anti-inflammatory activity of 15d-PGJ2. These findings reveal a novel cross-talk between translation and inflammatory response, and offer new approaches to develop anticancer and anti-inflammatory drugs that target translation factors including eIF4A.
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Woo Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Joon Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D018053:Arsenites / Q000378:metabolism; D002839:Chromans / Q000378:metabolism; D003517:Cyclopentanes / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000737:chemistry / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004640:Emetine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism; D007249:Inflammation / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D011454:Prostaglandins A / Q000378:metabolism; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D017670:Sodium Compounds / Q000378:metabolism; D000074019:T-Cell Intracellular Antigen-1; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D000893:Anti-Inflammatory Agents; D018053:Arsenites; D002839:Chromans; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D039102:Poly(A)-Binding Proteins; D011454:Prostaglandins A; D011500:Protein Synthesis Inhibitors; D017670:Sodium Compounds; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D047992:TNF Receptor-Associated Factor 2; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D016718:Arachidonic Acid; C017947:sodium arsenite; D039601:Eukaryotic Initiation Factor-4A; D000077288:Troglitazone; D015232:Dinoprostone; C013905:cyclopentenone; D015230:Prostaglandin D2; C039671:ciglitazone; C100573:prostaglandin A1; D004640:Emetine