Author response: Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency

Jo, Youngah; Kim, Steven S.; Garland, Kristina; Fuentes, Iris; DiCarlo, Lisa M.; Ellis, Jessie L; Fu, Xueyan; Booth, Sarah L.; Evers, B. Mark; DeBose‐Boyd, Russell A.

doi:10.7554/elife.54841.sa2

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“…Results of the current study considered together with those previously obtained in cultured cells and genetically-manipulated mice (Jo et al, 2019;Jo et al, 2020), designate the reductase ERAD pathway as a focal point in feedback control of intracellular levels of GGpp and other nonsterol isoprenoids. Sequestration of UBIAD1 in the ER of GGpp-deprived cells leads to the inhibition of reductase ERAD, which causes the protein to accumulate (indicated by green arrow in Figure 7).…”

Section: Discussionsupporting

confidence: 66%

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

Elsabrouty

Hwang

et al. 2021

eLife

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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.

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Section: Discussionsupporting

confidence: 66%