RNF45 (GP78) ja RNF145 molemmat E3 ubikitiiniligaasit johtavat HMGCoA reduktaasia ERAD:iin.

RNF 45 (GP78)   oli  aiemmin jo todettu  ubikitiiniligaasiksi,  joka ubikitinoi ja johti silppuriin HMG-CoA-reduktaasin  steroli-induktiosta. Tutkijat etsivät muita ubikitiiniligaaseja,  jotka suorittavat  samaa ja havaitsivat RNF145, josta on vähemmän artikkeleita saatavilla.

 https://www.ncbi.nlm.nih.gov/pubmed/29374057 
To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation,

J Biol Chem. 2018 Mar 16;293(11):4047-4055. doi: 10.1074/jbc.RA117.001260. Epub 2018 Jan 26. Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase. Jiang LY¹, Jiang W¹, Tian N¹, Xiong YN¹, Liu J¹, Wei J¹, Wu KY¹, Luo J¹, Shi XJ², Song BL³.

Abstract

Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate degradation of the rate-limiting cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by the endoplasmic reticulum membrane-associated (ERAD) protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO). To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation, we performed a small-scale short hairpin RNA-based screening targeting endoplasmic reticulum-localized E3s. We found that knockdown of both ring finger protein 145 (Rnf145) and gp78 (Rnf45)  genes abrogates sterol-induced degradation of HMGCR in CHO cells. We also observed that RNF145 interacts with Insig-1 and -2 proteins and ubiquitinates HMGCR. Moreover, the tetrapeptide sequence YLYF in the sterol-sensing domain and the Cys-537 residue in the RING finger domain were essential for RNF145 binding to Insigs and RNF145 E3 activity, respectively. Of note, amino acid substitutions in the YLYF or of Cys-537 completely abolished RNF145-mediated HMGCR degradation. In summary, our study reveals that RNF145, along with gp78 (RNF45) , promotes HMGCR degradation in response to elevated sterol levels and identifies residues essential for RNF145 function.