RNF144a induces ERK-dependent cell death under oxidative stress via downregulation of Vaccinia Related Kinase3

Abstract

Vaccinia-related kinase 3 (VRK3) has been reported to be a negative regulator of ERK that protects cells from persistent ERK activation and inhibits ERK dependent apoptosis. Here we report that the E3 ligase, RNF144a, promotes the degradation of VRK3 via poly-ubiquitination and thus affects VRK3-mediated ERK activity. Under oxidative stress, VRK3 migrates from the nucleus to the cytoplasm which increases its chance to interact with RNF144a, thereby promoting the degradation of VRK3. Overexpression of RNF144a increases ERK activity via downregulation of VRK3 and promotes ERK-dependent apoptosis. In contrast, depletion of RNF144a increases the protein level of VRK3 and protects cells from excessive ERK activity. These findings suggest that VRK3 protects cells by suppressing oxidative stress-induced ERK, and RNF144a sensitively regulates this process.