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E1A oncogene induced sensitization to NK cell induced apoptosis requires PIDD and Caspase-2. Cell Death Discov 2019;5:110

Date

07/10/2019

Pubmed ID

31285853

Pubmed Central ID

PMC6602934

DOI

10.1038/s41420-019-0189-z

Scopus ID

2-s2.0-85071074723

Abstract

Expression of the adenovirus E1A oncogene sensitizes tumor cells to innate immune rejection by NK cells. This increased NK sensitivity is only partly explained by an E1A-induced increase in target cell surface expression of NKG2D ligands. The post-recognition mechanisms by which E1A sensitizes cells to the apoptotic cell death response to NK injury remains to be defined. E1A sensitizes cells to apoptotic stimuli through two distinct mechanisms-repression of NF-I?B-dependent antiapoptotic responses and enhancement of caspase-2 activation and related mitochondrial injury. The current studies examined the roles of each of these post-NKG2D-recognition pathways in the increased sensitivity of E1A-positive target cells to NK killing. Sensitization to NK-induced apoptosis was independent of E1A-mediated repression of cellular NF-I?B responses but was dependent on the expression of both caspase-2 and the upstream, caspase-2 activating molecule, PIDD. Target cells lacking caspase-2 or PIDD expression retained E1A-induced increased expression of the NKG2D ligand, RAE-1. NK cell-induced mitochondrial injury of E1A-expressing cells did not require expression of the mitochondrial molecules, Bak or Bax. These results define a PIDD/caspase-2-dependent pathway, through which E1A sensitizes cells to NK-mediated cytolysis independently of and complementarily to E1A-enhanced NKG2D/RAE-1 ligand expression.

Author List

Radke JR, Routes JM, Cook JL

Author

John M. Routes MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin