Paper

CSDE1 is a Post-Transcriptional Regulator of the LDL Receptor

Li, Li, Nishino, Tomohiro, Shokat, Kevan, Chorba, John S, Padmanabhan, Arun, Sadagopan, Nandhini, Pampana, Akhil, Smith, Geoffrey A, Natarajan, Pradeep, Lee, Youngna Clara, Wu, Roland S, Lau, Bryan H, Pelonero, Angelo, Black, Brian L, Jain, Rajan, Srivastava, Deepak

2021

Overview

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current clinical therapies and known causes of familial hypercholesterolemia. We show that Cold Shock Domain-Containing Protein E1 (CSDE1) enhances hepatic LDLR mRNA decay via its 3′ untranslated region to regulate atherogenic lipoproteins in vivo. Using parallel phenotypic genome-wide CRISPR interference screens, we found 40 specific regulators of the LDLR left unidentified by observational human genetics. Among these, we show that CSDE1 regulates the LDLR at least as strongly as the mechanistically distinct pathways exploited by the best available clinical therapies: statins and PCSK9 inhibitors. Additionally, we show that hepatic gene silencing of Csde1 treats diet-induced dyslipidemia in mice better than that of Pcsk9. Our results reveal the therapeutic potential of manipulating a newly identified key factor in the post-transcriptional regulation of the LDLR mRNA for the prevention of cardiovascular disease. We anticipate that our approach of modelling a clinically relevant phenotype in a forward genetic screen, followed by mechanistic pharmacologic dissection and in vivo validation, will serve as a generalizable template for the identification of therapeutic targets in other human disease states. Competing Interest Statement P.N. reports investigator-initiated grant support from Amgen, Apple, and Boston Scientific, and personal fees from Apple, Blackstone Life Sciences, and Novartis, all unrelated to the present work. R.S.W. is an employee of Amgen, Inc. D.S. is the scientific cofounder, shareholder, and director of Tenaya Therapeutics, unrelated to the present work. K.M.S. has consulting agreements for the following companies involving cash and/or stock compensation: Black Diamond Therapeutics, BridGene Bioscences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Merck, Mitokinin, Petra Pharma, Revolution Medicines, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma). J.S.C. has received consulting fees from Gilde Healthcare and is an unpaid scientific advisor to Eko, both unrelated to this work. Footnotes * The current version reflects additional mechanistic details of CSDE1's action, in vivo validation of CSDE1 as a cholesterol regulating target in zebrafish and mice, and a therapeutic proof of principle of CSDE1 gene silencing for cholesterol lowering.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: 3' Untranslated regions / Arteriosclerosis / Atherosclerosis / Cardiovascular diseases / Cholesterol / Coronary artery disease / CRISPR / Genetic screening / Genomes / Genomics / Heart diseases / Hypercholesterolemia / Low density lipoprotein receptors / mRNA stability / Oncology / Phenotypes / Post-translation / RNA-binding protein / Transcription