Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4A.
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.
Kim
Woo Jae
WJ
Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
Kim
Joon Hyun
JH
Jang
Sung Key
SK
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
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