RNA-binding protein HuR interacts with thrombomodulin 5'untranslated region and represses internal ribosome entry site-mediated translation under IL-1 beta treatment.
Reduction in host-activated protein C levels and resultant microvascular thrombosis highlight the important functional role of protein C anticoagulant system in the pathogenesis of sepsis and septic shock. Thrombomodulin (TM) is a critical factor to activate protein C in mediating the anticoagulation and anti-inflammation effects. However, TM protein content is decreased in inflammation and sepsis, and the mechanism is still not well defined. In this report, we identified that the TM 5' untranslated region (UTR) bearing the internal ribosome entry site (IRES) element controls TM protein expression. Using RNA probe pulldown assay, HuR was demonstrated to interact with the TM 5'UTR. Overexpression of HuR protein inhibited the activity of TM IRES, whereas on the other hand, reducing the HuR protein level reversed this effect. When cells were treated with IL-1beta, the IRES activity was suppressed and accompanied by an increased interaction between HuR and TM 5'UTR. In the animal model of sepsis, we found the TM protein expression level to be decreased while concurrently observing the increased interaction between HuR and TM mRNA in liver tissue. In summary, HuR plays an important role in suppression of TM protein synthesis in IL-1beta treatment and sepsis.
Yeh
Chiu-Hung
CH
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Hung
Liang-Yi
LY
Hsu
Chin
C
Le
Shu-Yun
SY
Lee
Pin-Tse
PT
Liao
Wan-Lin
WL
Lin
Yi-Tseng
YT
Chang
Wen-Chang
WC
Tseng
Joseph T
JT
D020121:5' Untranslated Regions; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics*; D008954:Models, Biological; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*
D020121:5' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D053583:Interleukin-1beta; D016601:RNA-Binding Proteins; D018180:Thrombomodulin; D012313:RNA