Cellular Cholesterol Regulates Ubiquitination and Degradation of the Cholesterol Export Proteins ABCA1 and ABCG1

Hsieh, Victar; Kim, Mi-Jurng; Gelissen, Ingrid C.; Brown, Andrew; Sandoval, Cecilia; Hallab, Jeannette C.; Kockx, Maaike; Traini, Mathew; Jessup, Wendy; Kritharides, Leonard

doi:10.1074/jbc.m113.515890

Cited by 68 publications

(54 citation statements)

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“…According to previous studies, proteasome-and lysosomemediated degradation are the major pathways responsible for ABCA1 and ABCG1 protein stability (32)(33)(34)(35). The present study found that visfatin caused protein instability of ABCG1 through the proteasome-mediated degradation pathway (Fig.…”

Section: Discussionsupporting

confidence: 62%

Visfatin Promotes Foam Cell Formation by Dysregulating Cd36, Sra, Abca1, and Abcg1 Expression in RAW264.7 Macrophages

Lin

Jian

Kwok³

et al. 2016

Shock

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Section: Discussionsupporting

confidence: 62%

Visfatin Promotes Foam Cell Formation by Dysregulating Cd36, Sra, Abca1, and Abcg1 Expression in RAW264.7 Macrophages

Lin

Jian

Kwok³

et al. 2016

Shock

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“…Unexpectedly, the upregulation of ABCA1 expression by apoptotic GCs required the endogenous TXLNA in SCs (Figure 5d). ABCA1 degradation is mediated through ubiquitination, 21 which was evidenced in our study that 6-h incubation with apoptotic GCs substantially abolished ABCA1 ubiquitination in SCs (Figure 5e). However, in TXLNA-deficient SCs (Figure 5f), ABCA1 ubiquitination was constantly observed regardless of the presence of apoptotic GCs (Figure 5g).…”

Section: Resultssupporting

confidence: 54%

“…38,39 (iii) Ubiquitination has been associated with lysosomal degradation of cell surface-resident ABCA1 in HuH-7 and THP-1 macrophages. 21 (iv) Accumulated data evidence a frequent participation of ubiquitination in the metabolism of syntaxin. 40 By using an antibody-based ubiquitome analysis, Na et al 41 have demonstrated that a large number of synaptic proteins are modified by ubiquitination.…”

Section: Discussionmentioning

confidence: 98%

Unexpected requirement for a binding partner of the syntaxin family in phagocytosis by murine testicular Sertoli cells

Hou

et al. 2015

Cell Death Differ

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“…Our results suggest that NOD2 signaling causes intracellular lipid accumulation by promoting increased uptake of oxidized LDL probably through upregulation of scavenger receptors, but also by inhibiting HDL-mediated cholesterol efflux possibly through downregulation of ABCA1 in macrophages. The bell-shaped modulation of ABCA1 abundance by MDP is most likely a result of combination of the effects of increased cellular cholesterol content [32] due to increased uptake of oxidized LDL at low MDP concentrations and direct downregulation of ABCA1 at high MDP …”

mentioning

confidence: 99%

Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

et al. 2014

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Genetic studies have demonstrated that loss-of-function mutations in NOD2 are associated with several chronic inflammatory disorders, including Crohn's disease [9,10], whereas gain-offunction mutations in NOD2 correlate with Blau syndrome [11], and early-onset sarcoidosis [12], underscoring a crucial role for NOD2 in immune homoeostasis. However, the data on such mutations in cardiovascular disease are inconclusive [13][14][15].The involvement of NOD2 in inflammatory cardiovascular diseases was initially postulated based on the observations that vascular endothelial cells express low basal levels of NOD2 [16,17] and that depletion of RIP2 in myeloid cells regulates the development of atherosclerosis by induction of TLR4-mediated macropinocytosis of LDL in macrophages [18]. Moreover, Kwon et al. reported that lack of NOD2 signaling increases neointimal formation in mice after vascular injury [19]. We recently showed that stimulation of NOD2 in human carotid plaque results in rapid activation of the prostaglandin E2 pathway and IL-1β signaling, the first evidence supporting the involvement of NOD2 in human atherosclerosis [20]. Besides the traditional risk factors such as hypercholesterolemia, hypertension, obesity, and smoking, chronic infection with Porphyromonas gingivalis has been shown to promote atherosclerosis. In this regard, innate immune surveillance mechanism may provide essential protection against atherosclerosis. A recent study on ApoE −/− mice has revealed an indispensable role for NOD2 in protecting the mice from oral infection by Porphyromonas gingivalis, thereby restraining infection-mediated oral bone resorption, aortic inflammation, and plaque development [21]. Together, these findings indicate that NOD2 is involved in multiple aspects of cardiovascular diseases. However, whether NOD2 plays a direct role in atherosclerotic plaque development is not yet proven. This study was designed to elucidate the function of NOD2 signaling in atherosclerosis. By studying MDP-induced NOD2 signaling in atherosclerosis-prone mice and NOD2-deficient chimeric mice, we show that NOD2 promotes vascular inflammation and contributes to the expansion of the lipid-rich necrotic core in hyperlipidemic mice. Deploying an ex vivo culture system of human atherosclerotic plaque, we also characterized NOD2 signaling mechanisms in human atherosclerosis. Fig. 1). Results ActivationDespite no significant alteration in body weight and plasma cholesterol levels (Table 1), MDP-treated mice exhibited a dramatic increase in atherosclerosis in the aortic root compared with the controls (Fig. 1A and B). In association with the greater lesion burden, MDP-treated mice experienced enhanced vascular inflammation, as evidenced by significant upregulation of VCAM-1 and IL-6, and a tendency of elevation in TNF-α, MCP-1, IFN-γ, and IL-10 (Fig. 1C). Further, MDP increased the infiltration of CD68-positive macrophages and levels of COX2, implying macrophage activation in the lesion ( Fig. 1C-E). In parallel, the MDP treatment also resulted in...

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Cellular Cholesterol Regulates Ubiquitination and Degradation of the Cholesterol Export Proteins ABCA1 and ABCG1

Cited by 68 publications

References 54 publications

Visfatin Promotes Foam Cell Formation by Dysregulating Cd36, Sra, Abca1, and Abcg1 Expression in RAW264.7 Macrophages

Visfatin Promotes Foam Cell Formation by Dysregulating Cd36, Sra, Abca1, and Abcg1 Expression in RAW264.7 Macrophages

Unexpected requirement for a binding partner of the syntaxin family in phagocytosis by murine testicular Sertoli cells

Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid‐rich necrotic cores in hypercholesterolemic mice

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