Tripartite Motif‐Containing 27 Attenuates Liver Ischemia/Reperfusion Injury by Suppressing Transforming Growth Factor β–Activated Kinase 1 (TAK1) by TAK1 Binding Protein 2/3 Degradation

Abstract

Background and Aims Hepatic ischemia‐reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif‐containing (TRIM) 27 in hepatic I/R injury remains worthy of study. Approach and Results This study systemically evaluated the putative role of TRIM27/transforming growth factor β–activated kinase 1 (TAK1)/JNK (c‐Jun N‐terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down‐regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27‐KO mice) and hepatocyte‐specific Trim27 transgenic mice (Trim27‐HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R‐induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling. Conclusions TRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1‐JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R‐mediated hepatocellular damage in transplant recipients.

MicroRNA-26b-5p Targets DAPK1 to Reduce Intestinal Ischemia/Reperfusion Injury via Inhibition of Intestinal Mucosal Cell Apoptosis

“…Herein, we presented two major findings. First, we found that miR-26b-5p was downregulated in the intestinal mucosa during I/R and we confirmed the protective effect I/R-induced epithelial cell apoptosis is one primary mechanism driving I/R injury [26]. Previous work has demonstrated clear roles for miRNAs in the regulation of I/R-associated epithelial cell apoptosis [27].…”

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation

“…The regulation of Drp1 SUMOylation by augmenters of liver regeneration protected mitochondria from fission, rescuing hepatocytes from IRI-induced apoptosis [ 12 ]. Activating tripartite motif-containing 27 (TRIM27) prevented hepatocyte inflammation and apoptosis in hepatic IRI [ 13 ]. Hepatocyte-derived mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress-inducible protein, alleviated hepatic IRI via regulating ER stress-induced apoptosis in mice [ 14 ].…”

Emerging Roles of MHC Class I Region-Encoded E3 Ubiquitin Ligases in Innate Immunity

“…An immunohistological inspection indicated that when compared to healthy tissue, TRIM27 expression appeared higher in tissue derived from patients with Crohn disease (CD), implying that TRIM27 has a role in CD, which is a known NOD2-related inflammatory disease ( 30 ). Additionally, in a model of hepatic ischemia-reperfusion injury (IRI, which initiates from oxidative stress and inflammation caused by insufficient blood supply and subsequent reperfusion owing to trauma, resection or transplantation of the liver), TRIM27 alleviated liver damage and inflammation by suppressing the recruitment of TAK1 via TAB2/3 degradation ( 31 ). Moreover, TRIM27 interacts with multiple IKKs, including IKKα, IKKβ, IKKϵ and TBK1, to attenuate both NF-κB and IRF triggered IFN-β expression ( 32 ).…”