Kindlin-2 maintains liver homeostasis by regulating GSTP1–OPN-mediated oxidative stress and inflammation in mice

Abstract

Hepatocyte plays a principal role in preserving integrity of the liver homeostasis. Our recent study demonstrated that Kindlin-2, a focal adhesion protein that activates integrins and regulates cell-extracellular matrix interactions, plays an important role in regulation of liver homeostasis by inhibiting inflammation pathway; however, the molecular mechanism of how Kindlin-2 knockout activates inflammation is unknown. Here we show that Kindlin-2 loss largely downregulates the antioxidant glutathione S-transferase P 1 (GSTP1) in hepatocytes by promoting its ubiquitination and degradation via a mechanism involving protein-protein interaction. This causes overproduction of intracellular reactive oxygen species (ROS) and excessive oxidative stress in hepatocytes. Kindlin-2 loss upregulates osteopontin in hepatocytes partially due to upregulation of ROS and consequently stimulates overproduction of inflammatory cytokines and infiltration in liver. The molecular and histological deteriorations caused by Kindlin-2 deficiency are markedly reversed by systemic administration of an antioxidant N-acetylcysteine in mice. Taken together, Kindlin-2 plays a pivotal role in preserving integrity of liver function.