High level of blood cholesterol is a major risk factor for atherosclerosis.HMGCR is a rate-limiting enzyme in cholesterol biosynthetic pathway that also functions as the target of statin drugs.The sterol-stimulated degradation of HMGCR is an important negative feedback mechanism controlling cholesterol level.Gp78 is the primary E3 ubiquitin ligase promoting the degradation of HMGCR in liver cells.In the present study, we found that other E3s may also participate in HMGCR degradation in non-liver cells.To further screen for possible candidate(s), we constructed shRNA expression plasmids against potential E3 ubiquitin ligases and identified that RTM is a novel E3 ubiquitin ligase responsible for the degradation of HMGCR in Chinese hamster ovary (CHO) cells.In addition, RTM and gp78 were both involved in HMGCR degradation in non-liver cells.Furthermore, RTM displayed much higher ligase activity compared with that of gp78.