Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1

Abstract

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. The prenyltransferase has emerged as a key regulator of sterol-accelerated, endoplasmic reticulum (ER)-associated degradation (ERAD) of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Sterols induce binding of UBIAD1 to reductase, inhibiting its ERAD. Geranylgeraniol (GGOH), the alcohol derivative of GGpp, disrupts this binding and thereby stimulates ERAD of reductase and translocation of UBIAD1 to Golgi. We now show that overexpression of Type 1 polyisoprenoid diphosphate phosphatase (PDP1), which dephosphorylates GGpp and other isoprenyl pyrophosphates to corresponding isoprenols, abolishes protein geranylgeranylation as well as GGOH-induced ERAD of reductase and Golgi transport of UBIAD1. Conversely, these reactions are enhanced in the absence of PDP1. Our findings indicate PDP1-mediated hydrolysis of GGpp significantly contributes to a feedback mechanism that maintains optimal intracellular levels of the nonsterol isoprenoid.

Synthesis, function, and regulation of sterol and nonsterol isoprenoids

“…It is believed that the treated GGOH is converted to a biologically active form, GGPP, in cells by an unknown kinase. Our recent work indirectly supports this idea by showing that when the GGPP dephosphorylating enzyme is transiently overexpressed in vitro the effect of GGOH on HMGCR ERAD is blunted ( Elsabrouty et al, 2021 ) as described in Section 5.3 . The effect of GGOH was remarkably specific in that farnesol (FOH), the alcohol derivative of FPP, did not combine with sterols to accelerate HMGCR ERAD ( Sever et al, 2003a ).…”

“…Our work demonstrates that cells monitor nonsterol isoprenoid needs by using UBIAD1 as a sensor to screen levels of GGPP and thereby regulating ERAD of HMGCR ( Elsabrouty et al, 2021 ). These studies show GGPP is the most effective isoprenoid for regulating the UBIAD1-HMGCR complex dissociation, indicating the significant physiological roles of GGPP in regulating downstream functions such as vitamin K synthesis or modification of various proteins as shown in Figure 2 .…”

“…Our studies showed overexpression of PDP1 led to depletion of polyisoprenoid diphosphates FPP and GGPP, causing decreases in protein prenylation in targets such as Rho family GTPases, resulting in defective cytoskeletal organization and eventually cell death. The role of PDP1 in dephosphorylation of FPP and GGPP has a significant effect on the reduced prenylation of small GTPases and ERAD of HMGCR through UBIAD1 ( Elsabrouty et al, 2021 ). The knock down of PDP1 by RNA interference led to an increase in cellular GGPP levels, which facilitated the dissociation of UBIAD1 and HMGCR accelerating ERAD of HMGCR.…”

“…The other regulatory protein that cycles between the ER-Golgi is UBIAD1. It most likely utilizes COPII and COPI vesicles to cycle between the two organelles as evidenced in a simple budding assay from isolated microsomes where GGPP can induce the budding of UBIAD1 in small vesicles ( Aridor et al, 1998 ; Schumacher et al, 2016 ; Elsabrouty et al, 2021 ). Our studies show UBIAD1 resides in the Golgi under high GGPP conditions and is translocated to the ER when GGPP levels are low stabilizing a portion of HMGCR for continued isoprenoid synthesis.…”

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

“…GGPP can also be used for other purposes, such as the synthesis of vitamin K2 and ubiquinone which is utilised during oxidative phosphorylation. 1 , 2 Finally, following production of mammalian isoprenoids FPP and GGPP, prenyltransferases, such as farnesyl transferase (FTase) and geranylgeranyl transferases (GGTase I, GGTase II and GGTase III), catalyse the addition of the isoprenoids to target proteins. 3 , 4 , 5 This post‐translational modification is known as protein prenylation.…”