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A novel role of PSMB9 in endothelial cells and atherosclerosis: beyond its canonical function in immunoproteasome

Acta Pharmacologica Sinica (2024)Cite this article

The ubiquitin-proteasome system (UPS) constitutes a highly conserved protein degradation system in eukaryotic cells [1], comprising ubiquitin, ubiquitin enzymes, the 26 S proteasome, and deubiquitinating enzymes. The ubiquitin-proteasome degradation process involves a cascade reaction, in which proteins undergoing ubiquitination are ultimately degraded by the 26 S proteasome. This proteasome comprises a 20 S core subunit, 19 S regulatory subunit, and an 11 S regulatory subunit. The 20 S catalytic core of the proteasome houses three standard catalytic subunits: β1 (proteasome subunit-β type, PSMB6), β2 (PSMB7), and β5 (PSMB5) [2]. Upon stimulation by cytokines, such as interferon γ (IFN-γ), standard proteasome subunits can be substituted by immuno-proteasome subunits like β1i (PSMB9), β2i (PSMB10), and β5i (PSMB8), constituting an efficient proteolytic mechanism derived from the standard proteasome. Notably, PSMB9 exhibits caspase-like activity, while PSMB10 and PSMB8 exhibit trypsin-like and chymotrypsin-like activity [2]. PSMB9 plays a crucial role in various diseases including neurodegenerative conditions, malignant tumors, and autoimmune disorders. PSMB9-deficient mice exhibit spontaneous development of uterine leiomyosarcoma (uLMS) [3], accompanied by significant neurobehavioral dysfunction [4]. PSMB9 expression is absent in human uLMS [3]. However in Sjogren’s syndrome, the expression of PSMB9 is markedly elevated [5]. Nevertheless, the role of PSMB9 in cardiovascular diseases, particularly atherosclerosis, remains unclear.

Li et al. [6] have reported for the first time a potential role of PSMB9 in atherosclerosis by multiple experimental approaches including RNA-seq, RT-qPCR, and Western blot analyses and revealed a significant increase in PSMB9 expression in atherosclerotic plaques. To investigate the impacts of PSMB9 on atherosclerosis development, the authors generated Psmb9 and Apoe double-gene knockout mice. The results demonstrated that Psmb9 knockout restricted atherosclerosis plaques and vascular inflammation. These fundamental studies establish that PSMB9 exacerbate atherosclerosis, suggesting its potential as a pharmaceutical target. Interestingly, PSMB8 [7] and PSMB10 [8], the other two immune proteasomes, also promote atherosclerosis but mechanistically through a distinct pathway to regulate NF-κB-mediated inflammation.

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Fig. 1: Endothelial cell PSMB9-ZEB1-VCAM1/ICAM1 signaling pathway.

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  1. Lemole Center for Integrated Lymphatics and Vascular Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA

    Xiaolei Liu & Esteban Delgado

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  1. Xiaolei Liu
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Correspondence to Xiaolei Liu.

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Liu, X., Delgado, E. A novel role of PSMB9 in endothelial cells and atherosclerosis: beyond its canonical function in immunoproteasome. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01267-y

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