The E3 Ubiquitin Ligases, HUWE1 and NEDD4-1, Are Involved in the Post-translational Regulation of the ABCG1 and ABCG4 Lipid Transporters

Aleidi, Shereen M.; Howe, Vicky; Sharpe, Laura J.; Yang, Alryel; Rao, Geetha; Brown, Andrew; Gelissen, Ingrid C.

doi:10.1074/jbc.m115.675579

Cited by 46 publications

(46 citation statements)

References 44 publications

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“…Furthermore, the observations that both cholesterol efflux inhibition and ABCA1 depletion were prevented by down-regulation of Par1 or disruption of its gene suggest that Par1 mediates the effects of thrombin on cholesterol efflux and ABCA1 levels in both macrophages and smooth muscle cells. Some reports showed that the ABC transporters, particularly ABCA1 and ABCG1, were vulnerable for ubiquitination and degradation affecting cholesterol efflux (46,47). Although a few studies have shown a role for ubiquitination in the degradation of ABCA1 and ABCG1, the underlying mechanisms, particularly the role of E3 ubiquitin ligases in these effects, have not been explored.…”

Section: Discussionmentioning

confidence: 99%

Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3–mediated degradation of the ABCA1 transporter

Raghavan

Singh

Mani

et al. 2018

Journal of Biological Chemistry

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Although signaling of thrombin via its receptor protease-activated receptor 1 (Par1) is known to occur in atherothrombosis, its link to the actual pathogenesis of this condition is less clear. To better understand the role of thrombin-Par1 signaling in atherosclerosis, here we have studied their effects on cellular cholesterol efflux in mice. We found that by activating Par1 and cullin 3-mediated ubiquitination and degradation of ABC subfamily A member 1 (ABCA1), thrombin inhibits cholesterol efflux in both murine macrophages and smooth muscle cells. Moreover, disruption of the gene rescued ABCA1 from Western diet-induced ubiquitination and degradation and restored cholesterol efflux in apolipoprotein E-deficient (ApoE) mice. Similarly, the deletion diminished diet-induced atherosclerotic lesions in the ApoE mice. These observations for the first time indicate a role for thrombin-Par1 signaling in the pathogenesis of diet-induced atherosclerosis. We identify cullin 3 as a cullin-RING ubiquitin E3 ligase that mediates ABCA1 ubiquitination and degradation and thereby inhibits cholesterol efflux. Furthermore, compared with peripheral blood mononuclear cells (PBMCs) from ApoE mice, the PBMCs from ApoE:Par1 mice exhibited decreased trafficking to inflamed arteries of Western diet-fed ApoE mice. This finding suggested that besides inhibiting cholesterol efflux, thrombin-Par1 signaling also plays a role in the recruitment of leukocytes during diet-induced atherogenesis. Based on these findings, we conclude that thrombin-Par1 signaling appears to contribute to the pathogenesis of atherosclerosis by impairing cholesterol efflux from cells and by recruiting leukocytes to arteries.

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Section: Discussionmentioning

confidence: 99%

Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3–mediated degradation of the ABCA1 transporter

Raghavan

Singh

Mani

et al. 2018

Journal of Biological Chemistry

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“…Taking this rapid loss into account, the further disappearance of much of the rest of endogenous ABCG1 and GFP-G1 ( Fig 4 ) by 4-6h indicates that the remaining transporter is also not long-lived and is being lost at a rate that is quite rapid compared to recycling cell surface receptors such as TfR and the LDL receptor ( Fig 4 versus [ 50 , 51 ]). Thus, while ABCG1 is transported at appreciable levels in the β cell’s secretory and endocytic pathways, we suspect that its trafficking may be biased by sorting or modifications (e.g., ubiquitylation [ 52 ]) that favor lysosomal degradation over constitutive recycling.…”

Section: Discussionmentioning

confidence: 99%

Reinterpretation of the localization of the ATP binding cassette transporter ABCG1 in insulin-secreting cells and insights regarding its trafficking and function

et al. 2018

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The ABC transporter ABCG1 contributes to the regulation of cholesterol efflux from cells and to the distribution of cholesterol within cells. We showed previously that ABCG1 deficiency inhibits insulin secretion by pancreatic beta cells and, based on its immunolocalization to insulin granules, proposed its essential role in forming granule membranes that are enriched in cholesterol. While we confirm elsewhere that ABCG1, alongside ABCA1 and oxysterol binding protein OSBP, supports insulin granule formation, the aim here is to clarify the localization of ABCG1 within insulin-secreting cells and to provide added insight regarding ABCG1’s trafficking and sites of function. We show that stably expressed GFP-tagged ABCG1 closely mimics the distribution of endogenous ABCG1 in pancreatic INS1 cells and accumulates in the trans-Golgi network (TGN), endosomal recycling compartment (ERC) and on the cell surface but not on insulin granules, early or late endosomes. Notably, ABCG1 is short-lived, and proteasomal and lysosomal inhibitors both decrease its degradation. Following blockade of protein synthesis, GFP-tagged ABCG1 first disappears from the ER and TGN and later from the ERC and plasma membrane. In addition to aiding granule formation, our findings raise the prospect that ABCG1 may act beyond the TGN to regulate activities involving the endocytic pathway, especially as the amount of transferrin receptor is increased in ABCG1-deficient cells. Thus, ABCG1 may function at multiple intracellular sites and the plasma membrane as a roving sensor and modulator of cholesterol distribution, membrane trafficking and cholesterol efflux.

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“…Taking this rapid loss into account, the further disappearance of much of the rest of endogenous ABCG1 and GFP-G1 (Fig 4) by 4–6h indicates that the remaining transporter is also not long-lived and is being lost at a rate that is quite rapid compared to recycling cell surface receptors such as TfR and the LDL receptor (Fig 4 versus [47,48]). Thus, while ABCG1 is transported at appreciable levels in the β cell’s secretory and endocytic pathways, we suspect that its trafficking may be biased by sorting or modifications (e.g., ubiquitylation [49]) that favor lysosomal degradation over constitutive recycling.…”

Section: Discussionmentioning

confidence: 99%

Reinterpretation of the localization of the ATP binding cassette transporter ABCG1 in insulin-secreting cells and insights regarding its trafficking and function

Harris

Hussain

Inouye

et al. 2018

Preprint

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The ABC transporter ABCG1 regulates intracellular cholesterol. We showed previously that ABCG1 deficiency inhibits insulin secretion by pancreatic beta cells and, based on its immunolocalization to insulin granules, proposed its essential role in forming cholesterolenriched granule membranes. While we confirm elsewhere that ABCG1, alongside ABCA1 and oxysterol binding protein OSBP, supports insulin granule formation, the aim here is to update our localization and to provide added insight regarding ABCG1's trafficking and sites of function. We show that stably expressed GFP-tagged ABCG1 closely mimics the distribution of endogenous ABCG1 in pancreatic INS1 cells and accumulates in the trans-Golgi network (TGN), endosomal recycling compartment (ERC) and on the cell surface but not on insulin granules, early or late endosomes. Notably, ABCG1 is short-lived, and proteasomal and lysosomal inhibitors both decrease its degradation. Following blockade of protein synthesis, GFP-ABCG1 first disappears from the ER and TGN and later from the ERC and plasma membrane. Beyond aiding granule formation, our findings raise the prospect that ABCG1 may act beyond the TGN to regulate activities involving the endocytic pathway, especially as the amount of transferrin receptor is increased in ABCG1-deficient cells. Thus, ABCG1 may function at multiple intracellular sites and the plasma membrane as a roving sensor and modulator of cholesterol distribution and membrane trafficking. Running Title: Distribution and itinerant roles of ABCG1 1 Introduction 2 3In eukaryotic cells, the ATP Binding Cassette (ABC) transporters ABCA1 and ABCG1 4 are known to promote cholesterol export from cells and have been of substantial interest due to 5 their complementary roles alongside cholesterol uptake, biosynthesis and storage in maintaining 6 intracellular cholesterol homeostasis [1,2]. While these transporters are broadly expressed, their 7 levels are amplified in cells, e.g., macrophages and type-2 pneumocytes that are specialized for 8 processing and exporting lipids including cholesterol physiologically [3][4][5], and a major focus in 9 studying their actions has been on the mechanisms and pathways they use to transfer 10 cholesterol to plasma lipoproteins (reviewed in [6]). Several studies have also highlighted the 11 ability of ABCA1 and ABCG1 to promote cholesterol esterification and storage under conditions 12 that preclude cholesterol export [7][8][9] and to regulate processes that do not obviously relate 13 directly to either cholesterol export or storage including organization of plasma membrane lipids 14 (ABCA1: [10,11]), proliferation of immune and hematopoietic cells (ABCG1: [12][13][14]), and insulin 15 secretion (ABCs A1 and G1: [15][16][17][18]). ABCG1 has not been studied as extensively as ABCA1, 16 which gained early and enduring attention due to the link between its deficiency and Tangier 17 disease, where intracellullar cholesterol levels are increased and plasma levels of high density 18 lipoprotein are dramatically decreased [19...

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The E3 Ubiquitin Ligases, HUWE1 and NEDD4-1, Are Involved in the Post-translational Regulation of the ABCG1 and ABCG4 Lipid Transporters

Cited by 46 publications

References 44 publications

Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3–mediated degradation of the ABCA1 transporter

Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3–mediated degradation of the ABCA1 transporter

Reinterpretation of the localization of the ATP binding cassette transporter ABCG1 in insulin-secreting cells and insights regarding its trafficking and function

Reinterpretation of the localization of the ATP binding cassette transporter ABCG1 in insulin-secreting cells and insights regarding its trafficking and function

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