Role of PKC-dependent pathways in HNE-induced cell protein transport and secretion.
The beta isoforms of protein Kinase C (PKC) are closely involved in the regulation of cell protein transport and secretion. We have shown in different cellular types that treatment with HNE in a concentration range detectable in many pathophysiological conditions is able to induce selective activation of betaPKCs through direct interaction between the aldehyde and these isoenzymes. In isolated rat hepatocytes this specific isoenzyme activation plays a key role in the transport of procathepsin D from the trans-Golgi network to the endosomal-lysosomal compartment and in the exocytosis of mature cathepsin D. In NT2 neurons, HNE-mediated betaPKC activation induces an increase in intracellular amyloid beta production, without affecting full-length amyloid precursor protein expression. In a mouse macrophage-like cell line, the same beta isoform activation increases the release of the MCP-1 chemokine. Thus, pathophysiological HNE concentrations (0.1-1 microM) derived from a slight imbalance of the redox state are able to alter protein trafficking through beta PKC activation. These results suggest that mild oxidative stress and the PKC signal transduction pathway are closely involved in the pathophysiology of many diseases caused by changes in protein trafficking and release.
Marinari
Umberto Maria
UM
Department of Experimental Medicine, General Pathology Section, University of Genova, Via L.B. Alberti 2, Genova 16132, Italy.
Nitti
Mariapaola
M
Pronzato
Maria Adelaide
MA
Domenicotti
Cinzia
C
D000447:Aldehydes / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000378:metabolism*
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D018932:Chemokine CCL2; D011506:Proteins; D011493:Protein Kinase C; D002402:Cathepsin D; C027576:4-hydroxy-2-nonenal