TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation
Pingping Xiao, … , Huifen Dong, Rui Zhou
Pingping Xiao, … , Huifen Dong, Rui Zhou
Published December 8, 2021
Citation Information: JCI Insight. 2021;6(23):e149276. https://doi.org/10.1172/jci.insight.149276.
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Research Article Hepatology Inflammation

TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation

Abstract

Tristetraprolin (TTP), an important immunosuppressive protein regulating mRNA decay through recognition of the AU-rich elements (AREs) within the 3′-UTRs of mRNAs, participates in the pathogenesis of liver diseases. However, whether TTP regulates mRNA stability through other mechanisms remains poorly understood. Here, we report that TTP was upregulated in acute liver failure (ALF), resulting in decreased mRNA stabilities of CCL2 and CCL5 through promotion of N6-methyladenosine (m6A) mRNA methylation. Overexpression of TTP could markedly ameliorate hepatic injury in vivo. TTP regulated the mRNA stabilization of CCL2 and CCL5. Interestingly, increased m6A methylation in CCL2 and CCL5 mRNAs promoted TTP-mediated RNA destabilization. Moreover, induction of TTP upregulated expression levels of WT1 associated protein, methyltransferase like 14, and YT521-B homology N6-methyladenosine RNA binding protein 2, which encode enzymes regulating m6A methylation, resulting in a global increase of m6A methylation and amelioration of liver injury due to enhanced degradation of CCL2 and CCL5. These findings suggest a potentially novel mechanism by which TTP modulates mRNA stabilities of CCL2 and CCL5 through m6A RNA methylation, which is involved in the pathogenesis of ALF.

Authors

Pingping Xiao, Mingxuan Li, Mengsi Zhou, Xuejun Zhao, Cheng Wang, Jinglin Qiu, Qian Fang, Hong Jiang, Huifen Dong, Rui Zhou

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Figure 1

TTP protects against acute liver failure in APAP- or CCl4-treated mice.

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TTP protects against acute liver failure in APAP- or CCl4-treated mice. ...
(A) Expression of TTP protein was detected in the liver from APAP- or CCl4-induced mice for different times by immunohistochemistry (scale bar = 100 μm). Graph shows TTP protein levels ± SEM (n = 6). (B) Expression of TTP protein was detected in CCl4-challenged mice for different times with Western blot. Graph shows TTP protein levels ± SEM (n = 6). (C) Expression of TTP protein was detected in TTP-overexpression group following CCl4 injection by Western blot. Graph shows TTP protein levels ± SEM (n = 6). (D) The plasma ALT and AST level in mice (n = 6). (E) H&E staining of liver sections from TTP-overexpression mice induced by CCl4 for 24 and 48 hours. (Scale bar = 50 μm) (n = 6). (F) H&E staining of liver sections from AAV8-TTP–infected mice induced by CCl4 (scale bar = 50 μm) (n = 5). (G) The plasma ALT and AST level in mice (n = 6). (H) H&E staining of liver sections from TTP-knockdown mice induced by CCl4 (scale bar = 50 μm) (n = 5). (I) The plasma ALT and AST level in mice (n = 5). Data represent mean ± SEM from 3 independent experiments. Statistics by 1-way ANOVA with Dunnett’s multiple comparisons test (A and B), 2-way ANOVA with Tukey’s multiple comparisons test (C), 2-way repeated measure ANOVA with Tukey’s multiple comparisons test (D), and 2-tailed Student’s t test (G and I). *P < 0.05 versus Ctrl.