Novel mechanism of cyclic nucleotide crosstalk mediated by PKG-dependent proteasomal degradation of the Hsp90 client protein phosphodiesterase 3A.

Autor:	Zemskov EA; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA; Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA., Zemskova MA; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA., Wu X; Department of Medicine, University of Arizona Health Sciences, Tucson, Arizona, USA., Moreno Caceres S; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA., Caraballo Delgado D; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA., Yegambaram M; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA., Lu Q; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Miami, Florida, USA., Fu P; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Miami, Florida, USA., Wang T; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Miami, Florida, USA., Black SM; Center for Translational Science, Florida International University, Port St Lucie, Florida, USA; Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Miami, Florida, USA. Electronic address: stblack@fiu.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Oct; Vol. 300 (10), pp. 107723. Date of Electronic Publication: 2024 Aug 28.
DOI:	10.1016/j.jbc.2024.107723
Abstrakt:	Endothelial cAMP-specific phosphodiesterase PDE3A is one of the major negative regulators of the endothelial barrier function in acute lung injury models. However, the mechanisms underlying its regulation still need to be fully resolved. We show here that the PDE3A is a newly described client of the molecular chaperone heat shock protein 90 (hsp90). In endothelial cells (ECs), hsp90 inhibition by geldanamycin (GA) led to a disruption of the hsp90/PDE3A complex, followed by a significant decrease in PDE3A protein levels. The decrease in PDE3A protein levels was ubiquitin-proteasome-dependent and required the activity of the E3 ubiquitin ligase C terminus of Hsc70-interacting protein. GA treatment also enhanced the association of PDE3A with hsp70, which partially prevented PDE3A degradation. GA-induced decreases in PDE3A protein levels correlated with decreased PDE3 activity and increased cAMP levels in EC. We also demonstrated that protein kinase G-dependent phosphorylation of PDE3A at Ser 654 can signal the dissociation of PDE3A from hsp90 and PDE3A degradation. This was confirmed by endogenous PDE3A phosphorylation and degradation in 8-Br-cGMP- or 8-CPT-cGMP- and Bay 41-8543-stimulated EC and comparisons of WT- and phospho-mimic S 654 D mutant PDE3A protein stability in transiently transfected HEK293 cells. In conclusion, we have identified a new mechanism of PDE3A regulation mediated by the ubiquitin-proteasome system. Further, the degradation of PDE3A is controlled by the phosphorylation of S 654 and the interaction with hsp90. We speculate that targeting the PDE3A/hsp90 complex could be a therapeutic approach for acute lung injury. Competing Interests: Conflict of interest The authors declare they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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