The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1

Abstract

FBXO25 is one of the sixty-nine known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1 and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system (UPS). However, the substrates of most SCF E3 ligases remain unknown. Here, we applied an in chip ubiquitination screen using a human protein microarray to uncover putative substrates for the FBXO25 protein. Among several novel putative targets identified, the c-Fos protooncogene regulator ELK-1 was characterized as the first endogenous substrate for SCF1(FBXO25) E3 ligase. The FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells. In addition, FBXO25 overexpression suppressed induction of two ELK-1 target genes, c-Fos and EGR-1, in response to PMA. Together, our findings show that FBXO25 mediates ELK-1 degradation through the UPS and thereby plays a role in regulating the activation of ELK-1 pathway in response to mitogens. (AU)