Regulated degradation of HMG-CoA reductase, and integral membrane protein of the endoplasmic reticulum, in yeast

Numerous integral membrane proteins are degraded in the mammalian ER. HMG-CoA reductase (HMG-R), a key enzyme in the mevalonate pathway by which isoprenoids and sterols are synthesized, is one substrate of ER degradation. The degradation of HMG-R is modulated by feedback signals from the mevalonate...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of cell biology 1994-04, Vol.125 (2), p.299-312
Main Authors: Hampton, R.Y, Rine, J
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Biodegradation
Biological and medical sciences
Cellular biology
Coenzymes
DEGRADACION
DEGRADATION
Endopeptidases - metabolism
Endoplasmic Reticulum - enzymology
Enzyme Stability
Enzymes
Feedback
Fundamental and applied biological sciences. Psychology
Gene expression regulation
General aspects, investigation methods
Hydroxymethylglutaryl CoA Reductases - metabolism
Immunoprecipitation
ISOENZIMAS
ISOENZYME
Isoenzymes - metabolism
Membrane proteins
Membrane Proteins - metabolism
Mevalonic Acid - pharmacology
OXIDORREDUCTASAS
OXYDOREDUCTASE
Physiological regulation
Plasmids
Protein Prenylation
PROTEINAS
PROTEINE
Proteins
RETICULO ENDOPLASMATICO
RETICULUM ENDOPLASMIQUE
SACCHAROMYCES CEREVISIAE
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - ultrastructure
Sterols
Vacuoles - enzymology
Yeast
Yeasts
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Numerous integral membrane proteins are degraded in the mammalian ER. HMG-CoA reductase (HMG-R), a key enzyme in the mevalonate pathway by which isoprenoids and sterols are synthesized, is one substrate of ER degradation. The degradation of HMG-R is modulated by feedback signals from the mevalonate pathway. We investigated the role of regulated degradation of the two isozymes of HMG-R, Hmg1p and Hmg2p, in the physiology of Saccharomyces cerevisiae. Hmg1p was quite stable, whereas Hmg2p was rapidly degraded. Degradation of Hmg2p proceeded independently of vacuolar proteases or secretory traffic, indicating that Hmg2p degradation occurred at the ER. Hmg2p stability was strongly affected by modulation of the mevalonate pathway through pharmacological or genetic means. Decreased mevalonate pathway flux resulted in decreased degradation of Hmg2p. One signal for degradation of Hmg2p was a nonsterol, mevalonate-derived molecule produced before the synthesis of squalene. Genetic evidence indicated that a farnesylated protein may also be necessary for Hmg2p degradation. Studies with reporter genes demonstrated that the stability of each isozyme was determined by its noncatalytic NH2-terminal domain. Our data show that ER protein degradation is widely conserved among eukaryotes, and that feedback control of HMG-R degradation is an ancient paradigm of regulation
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.125.2.299