Inhibition of proteasome by bortezomib causes intracellular aggregation of hepatic serpins and increases the latent circulating form of antithrombin

Laboratory Investigation; a Journal of Technical Methods and Pathology
D Hernández-EspinosaJ Corral

Abstract

Conformational diseases include heterogeneous disorders sharing a similar pathological mechanism, leading to intracellular aggregation of proteins with toxic effects. Serpins are commonly involved in these diseases. These are structurally sensitive molecules that modify their folding under even minor genetic or environmental variations. Indeed, under normal conditions, the rate of misfolding of serpins is high and unfolded serpins must be degraded by the proteasome system. Our aim was to study the effects of bortezomib, a proteasome inhibitor, on conformationally sensitive serpins. The effects of bortezomib were analysed in patients with multiple myeloma, HepG2 cells, and Swiss mice, as well as in vitro. Levels, anti-FXa activity, heparin affinity, and conformational features of antithrombin, a relevant anticoagulant serpin, were analysed. Histological, ultrastructural features and immunohistological distribution of antithrombin and alpha1-antitrypsin (another hepatic serpin) were evaluated. We also studied the intracellular accumulation of conformationally sensitive (fibrinogen) or non-sensitive (prothrombin) hepatic proteins. The inhibition of the proteasome caused intracellular accumulation and aggregation of serpins within ...Continue Reading

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Jan 6, 2017·Respiratory Medicine Case Reports·Camille de SeynesC Raherison
Jul 30, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dacai XuJinbao Liu

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