https://www.ibiology.org/biochemistry/regulation-cholesterol-synthesis

Dr. Russell DeBose-Boyd describes cellular regulation of cholesterol synthesis, with a focus on endoplasmic reticulum-associated degradation (ERAD) of HMG CoA reductase.

Regulation of cholesterol synthesis is very important: cholesterol is a component of cell membranes and a precursor of steroid hormones and bile acids, yet high levels of cholesterol can be toxic to cells and can contribute to heart disease. Cells in our body obtain cholesterol one of two ways – by taking it up from the bloodstream (via low-density lipoprotein or LDL) or by synthesizing it intracellularly. In Part 1 of his iBioSeminar, Dr. Russell DeBose-Boyd provides an overview of cholesterol regulation with a focus on HMG CoA reductase, the rate-limiting enzyme of cholesterol synthesis. He describes how the effects of statins, drugs prescribed to lower LDL in the blood, are blunted due to the disruption of feedback control of HMG CoA reductase. In the presence of sterols, HMG CoA reductase protein stability is decreased. This sterol-accelerated degradation of HMG CoA reductase is dependent on the enzyme’s membrane domain in a process known as ER-associated degradation (ERAD). DeBose-Boyd describes his lab’s contributions to a model of HMG CoA reductase ERAD in which polyubiquitination of the enzyme in response to sterols is mediated by two proteins, Insig-1 and Insig-2, leading to its ERAD by the 26S proteasome.

In Part 2 of his talk, DeBose-Boyd introduces a rare genetic disorder known as Schnyder Corneal Dystrophy (SCD). SCD is characterized by accumulation of cholesterol in the corneas of affected individuals, indicating that the genetic defect in SCD may affect cholesterol synthesis. Mutations in the UBIAD1 gene cause SCD – therefore, DeBose-Boyd’s lab sought to understand the role of UBIAD1 in regulation of cholesterol metabolism. UBIAD1 mediates synthesis of Vitamin K2, which requires precursors from the cholesterol synthesis pathway. DeBose-Boyd shares evidence from his lab that UBIAD1 acts as a sensor for levels of the metabolite GGpp, which enhances sterol-mediated ERAD of HMG CoA reductase. In the absence of GGpp, UBIAD1 interacts with HMG CoA reductase in the ER membrane and blocks ERAD. In the presence of GGpp, however, UBIAD1 releases HMG CoA reductase, leading to its proteasomal degradation. DeBose-Boyd’s lab also discovered a fascinating spatial regulation of UBIAD1, whereby binding of UBIAD1 to GGpp causes UBIAD1 to accumulate in the Golgi apparatus and away from HMG CoA reductase in the ER. In the second half of his Part 2 lecture, DeBose-Boyd describes analyses of the SCD-associated mutation N102S in UBIAD1. The N102S mutation inhibits the interaction between UBIAD1 and GGpp, such that mutant UBIAD1 is unable to translocate from the ER to the Golgi in the presence of high GGpp. DeBose-Boyd’s lab predicted that the subsequent block of HMG CoA reductase ERAD by mutant UBIAD1 leads to the cholesterol over-accumulation observed in SCD patients. To test this hypothesis, they developed mice with a mutation in UBIAD1 that is equivalent to the N102S mutation observed in SCD patients. They found that, as predicted, mice with mutant UBIAD1 exhibited high levels of HMG CoA reductase protein in their tissues. Finally, they observed that the mutant mice developed corneal opacification, further suggesting that ERAD of HMG CoA reductase is blocked due to the UBIAD1 mutation.

Speaker Biography:
Dr. DeBose-Boyd began undergraduate studies at Southeastern Oklahoma State University where he obtained a BS in Chemistry with minors in Mathematics and Biology in 1993.

Upon completion of undergraduate studies, he was accepted into the Department of Biochemistry and Molecular Biology at the University of Oklahoma Health Sciences Center, and joined the laboratory of Richard D. Cummings, Ph. D. In 1998, he successfully defended his thesis entitled, “Identification, characterization, and molecular cloning of alpha 1,3 fucosyltransferases in parasitic and non-parasitic helminths.”

Following his defense, Dr. DeBose-Boyd joined the laboratory of Joseph L. Goldstein, M.D. and Michael S. Brown, M.D. at UT Southwestern Medical Center. After a successful postdoctoral fellowship, Drs. Goldstein and Brown invited Dr. DeBose-Boyd to join the faculty of the Molecular Genetics department as an Assistant Professor in 2003. He became an Established Investigator of the American Heart Association in 2005 and a W.M. Keck Distinguished Young Scholar in Medical Research in 2006. Dr. DeBose-Boyd was promoted to Associate Professor in 2007 and in 2009 he was appointed a Howard Hughes Medical Institute Early Career Scientist. In 2013, Dr. DeBose-Boyd was promoted to Professor and was named the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science in 2016.

http://www4.utsouthwestern.edu/moleculargenetics/pages/debose/lab.html