Linear ubiquitination modification of NR6A1 by LUBAC inhibits RIPK3 kinase activity and attenuates apoptosis of vascular smooth muscle cells

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  • 作者:Zhou Cai, Xin He, Shuai Liu, Yang Bai, Baihong Pan, Kemin Wu
  • 期刊:JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
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Nuclear receptor subfamily 6 group A member 1 (NR6A1) is involved in promoting the apoptotic process of vascular smooth muscle cells (VSMCs) which is a critical process involved in atherosclerosis, but the action mechanism remains to be determined. Therefore, we studied the underlying mechanisms by which NR6A1 accelerated VSMC apoptosis in atherosclerosis. An atherosclerosis model has been established in apolipoprotein E-deficient rats with a high-fat diet for 12 weeks, which was characterized by pathological aortic plaques, increased lipid deposition and collagen content in aortic tissues, and high cholesterol and triglycerides levels in the serum. NR6A1 was experimentally shown to increase at protein level rather than messenger RNA level in atherosclerotic rats. Immunofluorescence exhibited the main location of NR6A1 in the cell nucleus of rat aortic tissues. By performing ectopic expression experiments, NR6A1 was demonstrated to suppress the viability and expedite the apoptosis of VSMCs, corresponding to augmented caspase-3, caspase-8, and caspase-9 activities. It was further unraveled that NR6A1 could activate receptor-interacting serine/threonine-protein kinase 3 (RIPK3) by inducing its phosphorylation. Conversely, RIPK3 inhibitor GSK872 undermined the proapoptotic effect of NR6A1 on VSMCs. The co-immunoprecipitation assay identified that linear ubiquitin chain assembly complex (LUBAC) can be pulled down by NR6A1. Furthermore. LUBAC inhibited the expression of NR6A1 by promoting its linear ubiquitination, thereby dephosphorylating RIPK3 and consequently inhibiting the VSMC apoptosis. Overall, LUBAC-induced linear ubiquitination of NR6A1 can potentially arrest the apoptosis of VSMCs in atherosclerosis by downregulating RIPK3 and attenuating caspase activity. This finding suggests promising athero-protective targets by limiting VSMC apoptosis.

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