Talin1 Methylation Is Required for Neutrophil Infiltration and Lipopolysaccharide-Induced Lethality

Abstract

Talin1, a well-established integrin coactivator, is critical for the transmigration of neutrophils across the vascular endothelium into various organs and the peritoneal cavity during inflammation. Several posttranslational modifications of talin1 have been proposed to play a role in this process. In this study, we show that trimethylation of talin1 at Lys2454 by cytosolic Ezh2 is substantially increased in murine peritoneal neutrophils upon induction of peritonitis. By reconstituting talin1-deficient mouse myeloid cells with wild-type, methyl-mimicking, or unmethylatable talin1 variants, we demonstrate that methylation of talin1 at Lys2454 is important for integrin-dependent neutrophil infiltration into the peritoneal cavity. Furthermore, we show that treatment with an Ezh2 inhibitor or reconstitution of talin1-deficient myeloid cells with unmethylatable talin1 significantly reduces the number of organ-infiltrating neutrophils and protects mice from LPS-induced mortality.