4.8 Article

TNFAIP3 Interacting Protein 3 Is an Activator of Hippo-YAP Signaling Protecting Against Hepatic Ischemia/Reperfusion Injury

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HEPATOLOGY
卷 74, 期 4, 页码 2133-2153

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.32015

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资金

  1. National Key R&D Program of China [2016YFF0101504]
  2. National Science Foundation of China [82000550, 82000546, 81630011, 81970011]
  3. Hubei Science and Technology Support Project [2017BEC001]
  4. Fundamental Research Funds for the Central Universities [2042019kf0175]

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The study reveals that TNIP3 attenuates hepatic I/R injury by facilitating the ubiquitination and degradation of LATS2 and subsequent activation of YAP. This finding suggests that TNIP3 could serve as a promising therapeutic target for hepatic I/R injury to improve the prognosis of liver surgery.
Background and Aims Hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, causes a large proportion of early graft failure and organ rejection cases. The identification of key regulators of hepatic I/R injury may provide potential strategies to clinically improve the prognosis of liver surgery. Here, we aimed to identify the role of tumor necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in hepatic I/R injury and further reveal its immanent mechanisms. Approach and Results In the present study, we found that hepatocyte TNIP3 was markedly up-regulated in livers of both persons and mice subjected to I/R surgery. Hepatocyte-specific Tnip3 overexpression effectively attenuated I/R-induced liver necrosis and inflammation, but improved cell proliferation in mice, whereas TNIP3 ablation largely aggravated liver injury. This inhibitory effect of TNIP3 on hepatic I/R injury was found to be dependent on significant activation of the Hippo-YAP signaling pathway. Mechanistically, TNIP3 was found to directly interact with large tumor suppressor 2 (LATS2) and promote neuronal precursor cell-expressed developmentally down-regulated 4-mediated LATS2 ubiquitination, leading to decreased Yes-associated protein (YAP) phosphorylation at serine 112 and the activated transcription of factors downstream of YAP. Notably, adeno-associated virus delivered TNIP3 expression in the liver substantially blocked I/R injury in mice. Conclusions TNIP3 is a regulator of hepatic I/R injury that alleviates cell death and inflammation by assisting ubiquitination and degradation of LATS2 and the resultant YAP activation.TNIP3 represents a promising therapeutic target for hepatic I/R injury to improve the prognosis of liver surgery.

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