AAA-ATPase valosin-containing protein binds the transcription factor SREBP1 and promotes its proteolytic activation by rhomboid protease RHBDL4.

ABSTRACT: Valosin-containing protein (VCP) is a member of AAA-ATPase superfamily involved in various cellular functions. To investigate the pathophysiological role of VCP in metabolic disorders, we generated knock-in mice bearing an A232E mutation in VCP, a known human VCP pathogenic variant. When heterozygous mutant mice (A232E/+) were fed a high-fat diet, we observed that fatty liver was ameliorated and the proteolytic processing of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) was impaired. Further co-immunoprecipitation analysis in wildtype mice revealed interactions of VCP with SREBP1 and a rhomboid protease, RHBDL4, in the liver, and these interactions were attenuated in A232E/+ mice. Consistent with these results, we show that knockdown or chemical inhibition o

SUBMITTER: Shibuya K 

PROVIDER: S-EPMC9127370 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature