Protective effect of paraoxonase-2 against ER stress-induced apoptosis is lost upon disturbance of calcium-homeostasis

Sven Horke (1) , Ines Witte , Petra Wilgenbus , Sebastian Altenhöfer , Maximilian Krueger , Huige Li , Ulrich Förstermann

1 Department of Pharmacology

Paraoxonase-2 (PON2) is a ubiquitously expressed anti-oxidative protein, which is largely found in the endoplasmic reticulum (ER). 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 dithiotreitol), but not when ER stress was induced by disturbance of Ca2+ homeostasis (by thapsigargin or A23187). When analyzing 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 dithiotreitol resulted in increased PON2 mRNA and protein levels. In contrast, when ER stress was caused by thapsigargin or A23187, we observed a Ca2+-dependent active degradation of PON2 mRNA, elicited by its 5'untranslated region. In addition, thapsigargin and A23187 also induced PON2 protein degradation by a Ca2+-dependent calpain-mediated mechanism. Thus, we provide evidence that independent mechanisms mediate the degradation of PON2 mRNA and protein after disturbance of Ca2+ homeostasis. Further, because Ca2+-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.

Mots clés: Life Sciences

Sven Horke, Ines Witte, Petra Wilgenbus, Sebastian Altenhöfer, Maximilian Krueger, et al.. Protective effect of paraoxonase-2 against ER stress-induced apoptosis is lost upon disturbance of calcium-homeostasis. Biochemical Journal, 2008, 416 (3), pp.395-405. ⟨10.1042/BJ20080775⟩. ⟨hal-00479011⟩