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Reference: Garza RM, et al. (2009) Geranylgeranyl Pyrophosphate Is a Potent Regulator of HRD-dependent 3-Hydroxy-3-methylglutaryl-CoA Reductase Degradation in Yeast. J Biol Chem 284(51):35368-80

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Abstract


HMG-CoA reductase (HMGR), the rate-limiting enzymes of sterol synthesis, undergoes feedback-regulated ER degradation in both mammals and yeast. The yeast Hmg2p isozyme is subject to ubiquitin-mediated ER degradation by the HRD pathway. We had previously shown that alterations in cellular levels of the 15-carbon sterol pathway intermediate farnesyl pyrophosphate (FPP) cause increased Hmg2p ubiquitination and degradation. We now present evidence that the FPP-derived, 20-carbon molecule geranylgeranyl pyrophosphate (GGPP) is a potent endogenous regulator of Hmg2p degradation. This work was launched by the unexpected observation GGPP addition directly to living yeast cultures caused high potency and specific stimulation of Hmg2p degradation. This effect of GGPP was not recapitulated by FPP, GGOH, or related isoprenoids. GGPP-caused Hmg2p degradation met all the criteria for the previously characterized endogenous signal. The action of added GGPP did not require production of endogenous sterol molecules, indicating it did not act by causing the buildup of an endogenous pathway signal. Manipulation of endogenous GGPP by several means showed that naturally made GGPP controls Hmg2p stability. Analysis of the action of GGPP indicated that the molecule works upstream of retrotranslocation, and can directly alter the structure of Hmg2p. We propose that GGPP is the FPP-derived regulator of Hmg2p ubiquitination. Intriguingly, the sterol-dependent degradation of mammalian HMGR is similarly stimulated by addition of GGOH to intact cells, implying that a dependence on 20-carbon geranylgeranyl signals may be a common conserved feature of HMGR regulation, that may lead to highly specific therapeutic approaches for modulation of HMGR.

Reference Type
Journal Article
Authors
Garza RM, Tran PN, Hampton RY
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