Carma3 Protects from Liver Injury by Preserving Mitochondrial Integrity in Liver Sinusoidal Endothelial Cells

Abstract Carma3 is an intracellular scaffolding protein that can form complex with Bcl10 and Malt1 to mediate G protein–coupled receptor– or growth factor receptor–induced NF-κB activation. However, the in vivo function of Carma3 has remained elusive. Here, by establishing a Con A–induced autoimmune hepatitis model, we show that liver injury is exacerbated in Carma3−/− mice. Surprisingly, we find that the Carma3 expression level is higher in liver sinusoidal endothelial cells (LSECs) than in hepatocytes in the liver. In Carma3−/− mice, Con A treatment induces more LSEC damage, accompanied by severer coagulation. In vitro we find that Carma3 localizes at mitochondria and Con A treatment can trigger more mitochondrial damage and cell death in Carma3-deficient LSECs. Taken together, our data uncover an unrecognized role of Carma3 in maintaining LSEC integrity, and these results may extend novel strategies to prevent liver injury from toxic insults.