Thrombin-Par1 signaling axis disrupts COP9 signalosome subunit 3-mediated ABCA1 stabilization in inducing foam cell formation and atherogenesis

A Correction to this article was published on 12 January 2021

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Abstract

ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) play a vital role in promoting cholesterol efflux. Although, the dysregulation of these transporters was attributed as one of the mechanisms of atherogenesis, what renders their dysfunction is not well explored. Previously, we have reported that thrombin without having any effect on ABCG1 levels depletes ABCA1 levels affecting cholesterol efflux. In this study, we explored the mechanisms underlying thrombin-induced depletion of ABCA1 levels both in macrophages and smooth muscle cells. Under normal physiological conditions, COP9 signalosome subunit 3 (CSN3) was found to exist in complex with ABCA1 and in the presence of proatherogenic stimulants such as thrombin, ABCA1 was phosphorylated and dissociated from CSN3, leading to its degradation. Forced expression of CSN3 inhibited thrombin-induced ABCA1 ubiquitination and degradation, restored cholesterol efflux and suppressed foam cell formation. In Western diet (WD)-fed ApoE−/− mice, CSN3 was also disassociated from ABCA1 otherwise remained as a complex in Chow diet (CD)-fed ApoE−/− mice. Interestingly, depletion of CSN3 levels in WD-fed ApoE−/− mice significantly lowered ABCA1 levels, inhibited cholesterol efflux and intensified foam cell formation exacerbating the lipid laden atherosclerotic plaque formation. Mechanistic studies have revealed the involvement of Par1-Gα12-Pyk2-Gab1-PKCθ signaling in triggering phosphorylation of ABCA1 and its disassociation from CSN3 curtailing cholesterol efflux and amplifying foam cell formation. In addition, although both CSN3 and ABCA1 were found to be colocalized in human non-lesion coronary arteries, their levels were decreased as well as dissociated from each other in advanced atherosclerotic lesions. Together, these observations reveal for the first time an anti-atherogenic role of CSN3 and hence, designing therapeutic drugs protecting its interactions with ABCA1 could be beneficial against atherosclerosis.

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Fig. 1: Dissociation of CSN3 from ABCA1 in macrophages in response to thrombin and ApoE−/− mice in response to WD feeding.
Fig. 2: CSN3 blocks thrombin-induced ABCA1 depletion, rescues cholesterol efflux, and inhibits foam cell formation.
Fig. 3: Downregulation of CSN3 depletes ABCA1 levels, inhibits cholesterol efflux, and enhances foam cell formation in WD-fed ApoE−/− mice.
Fig. 4: Depletion of CSN3 levels exacerbates WD-induced atherosclerotic lesions in ApoE−/− mice.
Fig. 5: Role of Par1-Gα12-Pyk2-Gab1-PKCθ signaling in thrombin-induced disassociation of ABCA1 and CSN3 complex and inhibition of cholesterol efflux and foam cell formation.
Fig. 6: Thrombin induces dissociation of CSN3 from ABCA1, leading to ABCA1 depletion and inhibition of cholesterol efflux in MASMCs.
Fig. 7: Role of Par1-Gα12-Pyk2-Gab1-PKCθ signaling in thrombin-induced disassociation of CSN3 from ABCA1 and inhibition of cholesterol efflux and foam cell formation in MASMCs.
Fig. 8: Depletion of CSN3 and ABCA1 levels in advanced atherosclerotic lesions of human coronary arteries.

Change history

  • 12 January 2021

    A Correction to this paper has been published: https://doi.org/10.1038/s41418-020-00718-3.

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Acknowledgements

The present work was supported by grants HL103575 and HL069908 from National Institutes of Health to GN Rao.

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Correspondence to Gadiparthi N. Rao.

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Edited by: D. Aberdam

The original online version of this article was revised: The original version of this article unfortunately contained a mistake in one of the author names (A. Wayne Orr). The surname is ‘Orr’, not ‘Wayne Orr’.

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Boro, M., Govatati, S., Kumar, R. et al. Thrombin-Par1 signaling axis disrupts COP9 signalosome subunit 3-mediated ABCA1 stabilization in inducing foam cell formation and atherogenesis. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-00623-9

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