Protective effect of paraoxonase-2 against endoplasmic reticulum stress-induced apoptosis is lost upon disturbance of calcium homoeostasis.

PON2 (paraoxonase-2) is a ubiquitously expressed antioxidative protein which is largely found in the ER (endoplasmic reticulum). Addressing the cytoprotective functions of PON2, we observed that PON2 overexpression provided significant resistance to ER-stress-induced caspase 3 activation when the ER stress was induced by interference with protein modification (by tunicamycin or dithiothreitol), but not when ER stress was induced by disturbance of Ca(2+) homoeostasis (by thapsigargin or A23187). When analysing the underlying molecular events, we found an activation of the PON2 promoter in response to all tested ER-stress-inducing stimuli. However, only tunicamycin and dithiothreitol resulted in increased PON2 mRNA and protein levels. In contrast, when ER stress was caused by thapsigargin or A23187, we observed a Ca(2+)-dependent active degradation of PON2 mRNA, elicited by its 5'-untranslated region. In addition, thapsigargin and A23187 also induced PON2 protein degradation by a Ca(2+)-dependent calpain-mediated mechanism. Thus we provide evidence that independent mechanisms mediate the degradation of PON2 mRNA and protein after disturbance of Ca(2+) homoeostasis. Furthermore, because Ca(2+)-disturbance induces ER stress, but abrogates the otherwise protective function of PON2 against ER-stress-induced apoptosis, we propose that the underlying cause of ER stress determines the efficacy of putative cellular defence mechanisms.

[1]  B. Brüne,et al.  A23187, ionomycin and thapsigargin upregulate mRNA of HIF‐1α via endoplasmic reticulum stress rather than a rise in intracellular calcium , 2008, Journal of cellular physiology.

[2]  R. Haley,et al.  Dominant Role of Paraoxonases in Inactivation of the Pseudomonas aeruginosa Quorum-Sensing Signal N-(3-Oxododecanoyl)-l-Homoserine Lactone , 2008, Infection and Immunity.

[3]  M. Aviram,et al.  Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPAR gamma and AP-1 pathway activation. , 2007, Atherosclerosis.

[4]  Chao Zhang,et al.  IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response , 2007, Science.

[5]  R. Eliakim,et al.  Paraoxonases are associated with intestinal inflammatory diseases and intracellularly localized to the endoplasmic reticulum. , 2007, Free radical biology & medicine.

[6]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[7]  D. Shih,et al.  Adenovirus-Mediated Expression of Human Paraoxonase 3 Protects Against the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[8]  B. La Du,et al.  Estrogen esters as substrates for human paraoxonases. , 2007, Archives of biochemistry and biophysics.

[9]  U. Förstermann,et al.  Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress–Induced Caspase Activation , 2007, Circulation.

[10]  D. Shih,et al.  Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[11]  A. Nantel,et al.  Calnexin-dependent regulation of tunicamycin-induced apoptosis in breast carcinoma MCF-7 cells , 2007, Cell Death and Differentiation.

[12]  S. Reddy,et al.  Adenovirus mediated expression of human paraoxonase 2 protects against the development of atherosclerosis in apolipoprotein E-deficient mice. , 2006, Molecular genetics and metabolism.

[13]  Aiqing He,et al.  The Unfolded Protein Response Is an Important Regulator of Inflammatory Genes in Endothelial Cells , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[14]  Aldons J Lusis,et al.  Paraoxonase-2 Deficiency Aggravates Atherosclerosis in Mice Despite Lower Apolipoprotein-B-containing Lipoproteins , 2006, Journal of Biological Chemistry.

[15]  C. Misquitta,et al.  Control of protein expression through mRNA stability in calcium signalling. , 2006, Cell calcium.

[16]  R. Korneluk,et al.  Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: a role for the IAPs. , 2006, Experimental cell research.

[17]  M. Niwa,et al.  Intrinsic capacities of molecular sensors of the unfolded protein response to sense alternate forms of endoplasmic reticulum stress. , 2006, Molecular biology of the cell.

[18]  U. Förstermann,et al.  Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace , 2006, Circulation.

[19]  G. Werstuck,et al.  Mechanisms linking diabetes mellitus to the development of atherosclerosis: a role for endoplasmic reticulum stress and glycogen synthase kinase-3. , 2006, Canadian journal of physiology and pharmacology.

[20]  R. Kaufman,et al.  The unfolded protein response , 2006, Neurology.

[21]  T. Hsiai,et al.  Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: implication of NADPH oxidase. , 2005, Free radical biology & medicine.

[22]  Yibin Wang,et al.  Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor , 2005, The Journal of cell biology.

[23]  R. Sunahara,et al.  Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificitiess⃞s⃞ The online version of this article (available at http://www.jlr.org) contains additional text, figures, and references. Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M , 2005, Journal of Lipid Research.

[24]  L. Ruddock,et al.  The human protein disulphide isomerase family: substrate interactions and functional properties , 2005, EMBO reports.

[25]  M. Aviram,et al.  Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. , 2004, Free radical biology & medicine.

[26]  E. Cadenas,et al.  Kinetic analysis of thapsigargin-induced thymocyte apoptosis. , 2004, Free radical biology & medicine.

[27]  M. Cnop,et al.  Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-κB and Endoplasmic Reticulum Stress , 2004 .

[28]  J. Keaney,et al.  Role of oxidative modifications in atherosclerosis. , 2004, Physiological reviews.

[29]  M. Gorospe,et al.  Global mRNA Stabilization Preferentially Linked to Translational Repression during the Endoplasmic Reticulum Stress Response , 2004, Molecular and Cellular Biology.

[30]  P. Rath,et al.  Induction of the Interferon-Inducible RNA-Degrading Enzyme, RNase L by Stress-Inducing Agents in the Human Cervical Carcinoma Cells , 2004, RNA biology.

[31]  K. Griendling,et al.  Reactive oxygen species in the vasculature: molecular and cellular mechanisms. , 2003, Hypertension.

[32]  George Kuriakose,et al.  The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages , 2003, Nature Cell Biology.

[33]  Hiderou Yoshida,et al.  A time-dependent phase shift in the mammalian unfolded protein response. , 2003, Developmental cell.

[34]  R. Kaufman,et al.  The mammalian unfolded protein response. , 2003, Annual review of biochemistry.

[35]  D. Ron,et al.  Endoplasmic reticulum stress and the development of diabetes: a review. , 2002, Diabetes.

[36]  Takashi Kudo,et al.  The Unfolded Protein Response Is Involved in the Pathology of Alzheimer's Disease , 2002, Annals of the New York Academy of Sciences.

[37]  A. Tward,et al.  Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice , 2002, Circulation.

[38]  Xi Chen,et al.  ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. , 2002, Developmental cell.

[39]  S. Reddy,et al.  Paraoxonase-2 Is a Ubiquitously Expressed Protein with Antioxidant Properties and Is Capable of Preventing Cell-mediated Oxidative Modification of Low Density Lipoprotein* , 2001, The Journal of Biological Chemistry.

[40]  R. Neumar,et al.  Brain ischemia and reperfusion: molecular mechanisms of neuronal injury , 2000, Journal of the Neurological Sciences.

[41]  R. Kaufman,et al.  Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. , 2000, The Journal of biological chemistry.

[42]  Anne Bertolotti,et al.  Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response , 2000, Nature Cell Biology.

[43]  E. Wąsowicz,et al.  An excess concentration of oxysterols in the plasma is cytotoxic to cultured endothelial cells. , 2000, Atherosclerosis.

[44]  Hiderou Yoshida,et al.  Identification of the cis-Acting Endoplasmic Reticulum Stress Response Element Responsible for Transcriptional Induction of Mammalian Glucose-regulated Proteins , 1998, The Journal of Biological Chemistry.

[45]  B. La Du,et al.  The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. , 1996, Genomics.

[46]  D. Y. Thomas,et al.  Calnexin: a membrane-bound chaperone of the endoplasmic reticulum. , 1994, Trends in biochemical sciences.

[47]  K. Abromeit.  Music Received , 2023, Notes.

[48]  T. Chin,et al.  Dual effect of thapsigargin on cell death in porcine aortic smooth muscle cells. , 2007, American journal of physiology. Cell physiology.

[49]  W. Bowen,et al.  Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response , 2006 .

[50]  Robert C. Wolpert,et al.  A Review of the , 1985 .