Differential use of E2 ubiquitin conjugating enzymes for regulated degradation of the rate-limiting enzymes HMGCR and SQLE in cholesterol biosynthesis

Tan, Josephine M.E.; Cook, Emma C. L.; Berg, Marlene van den; Scheij, Saskia; Zelcer, Noam; Loregger, Anke

doi:10.1016/j.atherosclerosis.2018.12.008

Cited by 35 publications

(22 citation statements)

References 34 publications

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“…Consistent with this, we also did not observe changes in low-density lipoprotein (LDL) uptake, a close proxy of LDL receptor (LDLR) levels and function (Figure S1A). Similarly, we did not observe a change in the expression of the E2 ubiquitin conjugating enzyme UBE2J2, which we have recently shown to be the cognate E2 used by MARCH6 to promote SQLE ubiquitylation (Loregger et al, 2020;Tan et al, 2019). These results are in line with the post-transcriptional regulation of SQLE by MARCH6 in ECs, as we and others have observed in other model cell systems (Chua et al, 2019;Gill et al, 2011;Loregger et al, 2015;Zelcer et al, 2014).…”

Section: March6 Governs Sqle and Cholesterol Levels In Ecssupporting

confidence: 91%

The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

et al. 2020

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Section: March6 Governs Sqle and Cholesterol Levels In Ecssupporting

confidence: 91%

The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

et al. 2020

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“…MARCH6 is the human ortholog of yeast Doa10 (46), whereas Ube2J2 and Ube2G2 are the human orthologs of yeast Ubc6 and Ubc7, respectively (47,48). During this study, two independent groups showed that Ube2J2 is needed to degrade endogenous full-length SM (49,50). Given that both human Ube2J2 and yeast Ubc6 have been shown to attach ubiquitin on serine residues (42, 51), we hypothesized Ube2J2 regulates SM by targeting the SM N100 degron through serine ubiquitination.…”

Section: Evidence Of Serine Ubiquitination From Destabilizing Effectsmentioning

confidence: 91%

“…The degradation machinery regulating yeast and mammalian SM is evolutionarily conserved. Ube2J2 and MARCH6 are needed for degradation of SM (22,49,50). The yeast orthologs of Ube2J2 and MARCH6 are Ubc6 (47) and Doa10 (43,46), which are required for degrading yeast SM (commonly known as Erg1) (45).…”

Section: Serine Ubiquitination and Cholesterol Regulationmentioning

confidence: 99%

Non-canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase

Chua¹,

Hart‐Smith²,

Brown

2019

Journal of Biological Chemistry

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Squalene monooxygenase (SM) is a rate-limiting enzyme in cholesterol synthesis. The region comprising the first 100 amino acids, termed SM N100, represents the shortest cholesterol-responsive degron and enables SM to sense excess cholesterol in the endoplasmic reticulum (ER) membrane. Cholesterol accelerates the ubiquitination of SM by membrane-associated ring-CH type finger 6 (MARCH6), a key E3 ubiquitin ligase involved in ER-associated degradation. However, the ubiquitination site required for cholesterol regulation of SM N100 is unknown. Here, we used SM N100 fused to GFP as a model degron to recapitulate cholesterol-mediated SM degradation and show that neither SM lysine residues nor the N terminus impart instability. Instead, we discovered four serines (Ser-59, Ser-61, Ser-83, and Ser-87) that are critical for cholesterol-accelerated degradation, with MS analysis confirming Ser-83 as a ubiquitination site. Notably, these two clusters of closely spaced serine residues are located in disordered domains flanking a 12-amino acid-long amphipathic helix (residues Gln-62–Leu-73) that together confer cholesterol responsiveness. In summary, our findings reveal the degron architecture of SM N100, introducing the role of non-canonical ubiquitination sites and deepening our molecular understanding of how SM is degraded in response to cholesterol.

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“…In the current study, we clearly demonstrated, for the fi rst time, that serum from patients with signifi cant coronary atherosclerosis (as indicated by CT angiography), substantially increased J774A.1 macrophage cholesterol content.Although serum cholesterol and LDL-C levels were similar in all three CTCA groups, incubation of macrophages with serum derived from atherogenic patients resulted in increased cellular cholesterol levels compared to less atherogenic patients, or to subjects with no atherosclerosis. This effect could be attributed to the signifi cant increase in cholesterol biosynthesis rate, secondary to the observed up-regulation of HMGCR (rate limiting enzyme in cholesterol biosynthesis) expression[20]. Similarly, it was previously shown that serum taken from patients with angiographically coronary atherosclerosis induced cholesterol deposition in smooth muscle cells from human aortic intima[14].…”

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confidence: 87%

Serum from patients with chest pain and significant atherosclerosis resulted in macrophage cholesterol accumulation

Dawood¹,

Volkova²,

Namouz³

et al. 2020

J Cardiovasc Med Cardiol

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Aims: The aim of our study was to analyze the effect of serum derived from patients with chest pain, with or without signifi cant atherosclerosis, on J774A.1 macrophages cholesterol metabolism. Methods: Thirty-nine patients with chest pain underwent CT Coronary Angiography (CTCA) to assess atherosclerosis. They were divided into three groups (n=13 for each group), according to extent of Coronary Artery Disease (CAD): No disease (NCAD), Non-signifi cant (NSCAD), or signifi cant CAD (SCAD). Results: Serum total cholesterol level was similar in all three groups, whereas the SCAD group had the lowest serum HDL level and highest serum triglyceride levels, compared with the other groups. The patient's serum (30μl) was incubated with J774 macrophages for 18h. Cellular cholesterol mass was found to be signifi cantly higher by 44 percent in SCAD patients compared to NCAD patients, and by 23 percent compared to NSCAD patients. In parallel, we observed a signifi cant enhanced cholesterol biosynthesis rate by 53 percent in macrophages treated with serum from the SCAD patients, as compared to NCAD patients, or by 17 percent when compared to the NSCAD patients. In accordance with the above results, HMGCR (the rate limiting enzyme in cholesterol biosynthesis) expression was signifi cantly upregulated in macrophages treated with serum from SCAD patients, in comparison to NCAD or NSCAD patients. Conclusion: These results clearly demonstrate high macrophage atherogenicity for serum harvested from patients with signifi cant atherosclerosis.

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Differential use of E2 ubiquitin conjugating enzymes for regulated degradation of the rate-limiting enzymes HMGCR and SQLE in cholesterol biosynthesis

Cited by 35 publications

References 34 publications

The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

Non-canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase

Serum from patients with chest pain and significant atherosclerosis resulted in macrophage cholesterol accumulation

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