PIDD-dependent activation of caspase-2-mediated mitochondrial injury in E1A-induced cellular sensitivity to macrophage nitric oxide-induced apoptosis

Abstract

Expression of the adenovirus E1A oncogene sensitizes tumor cells to innate immune rejection by apoptosis induced by macrophage-produced tumor necrosis factor (TNF)-α and nitric oxide (NO). E1A sensitizes cells to TNF-α and NO through two distinct mechanisms, by repressing NF-κB-dependent antiapoptotic responses and enhancing caspase-2 activation and mitochondrial injury, respectively. The mechanisms through which E1A enhances caspase-2 activation in response to NO were unknown. Here, we report that E1A-induced sensitization to NO-induced apoptosis is dependent on expression of PIDD (p53-inducible protein with a death domain) and enhancement of primary immunodeficiency diseases (PIDD) processing for formation of the PIDDosome, the core component of the caspase-2 activation complex. NO-induced apoptosis in E1A-expressing cells did not require expression Bak or Bax, indicating that NO-induced caspase-2-mediated mitochondrial injury does not proceed through the activities of typical, proapoptotic Bcl-2 family members that induce mitochondrial cytochrome C release. These results define a PIDD-dependent pathway, through which E1A enhances casapse-2-mediated mitochondrial injury, resulting in increased sensitivity of mammalian cells to macrophage-induced, NO-mediated apoptosis.

E1A oncogene induced sensitization to NK cell induced apoptosis requires PIDD and Caspase-2

“…The data presented here define PIDD–caspase-2 as the key, post-recognition cellular pathway through which E1A enhances target cell susceptibility to NK-cell-mediated cytolytic activity, as a complementary mechanism to E1A-induced increased expression of NKG2D ligands 6 . These results and our previously reported data also suggest that PIDD-dependent caspase-2 activation enhancement is a common cellular mechanism through which E1A sensitizes cells to a variety of stimuli of the intrinsic apoptosis pathway, including macrophage-NO and proapoptotic chemotherapeutic drugs 11,12,16 .…”

“…5c, d). These data and those published previously strongly suggest that E1A expression enhances caspase-2 activation through the PIDDosome in response to a variety of intrinsic apoptotic injuries 11,16 , including those mediated by NK cells.…”

“…We have reported that induction of the intrinsic apoptotic pathway in E1A-expressing cells by NO and chemotherapeutic drugs requires PIDD-dependent activation of caspase-2 (refs. 11,12,16 ). The current studies extend that mechanistic pattern to NK cell killing of E1A-expressing target cells (Fig.…”

“…E1A sensitizes cells to apoptosis induced through the extrinsic apoptosis pathway (triggered by TNF, Fas ligand, and TRAIL) by repressing transcription of NF-κB-dependent antiapoptotic gene expression 13–15 . We have also demonstrated that E1A sensitizes cells to apoptosis from intrinsic pathway injuries (chemotherapeutic agents and nitric oxide (NO)) through NF-κB-independent cellular mechanisms but is dependent on enhanced PIDD-mediated activation of caspase-2 11,12,16 .…”

Mechanism of Action of Prethioviridamide, an Anticancer Ribosomally Synthesized and Post-Translationally Modified Peptide with a Polythioamide Structure

“…34,35 E1A makes cells sensitive to nitric oxide by inducing mitochondrial dysfunction−mediated apoptosis. 36 We observed that mitochondrial morphology was different in 3Y1 and E1A-3Y1 cells. Therefore, it is possible that expression of E1A could modify mitochondrial functions or structures, making cells more sensitive to mitochondrial stresses such as prethioviridamide treatment.…”