Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis

Faraaz B. Chekeni, Michael R. Elliott, Joanna K. Sandilos, Scott F. Walk, Jason M. Kinchen, Eduardo R. Lazarowski, Allison J. Armstrong, Silvia Penuela, Dale W. Laird, Guy S. Salvesen, Brant E. Isakson, Douglas A. Bayliss, Kodi S. Ravichandran

Research output: Contribution to journalArticlepeer-review

724 Scopus citations

Abstract

Apoptotic cells release 'find-me' signals at the earliest stages of death to recruit phagocytes. The nucleotidesATP andUTPrepresent one class of find-me signals, but their mechanism of release is not known. Here, we identify the plasma membrane channel pannexin 1 (PANX1) as a mediator of find-me signal/nucleotide release from apoptotic cells. Pharmacological inhibition and siRNA-mediated knockdown of PANX1 led to decreased nucleotide release and monocyte recruitment by apoptotic cells. Conversely, PANX1 overexpression enhanced nucleotide release from apoptotic cells and phagocyte recruitment. Patch-clamp recordings showed that PANX1 was basally inactive, and that induction of PANX1 currents occurred only during apoptosis. Mechanistically, PANX1 itself was a target of effector caspases (caspases 3 and 7), and a specific caspase-cleavage site within PANX1 was essential for PANX1 function during apoptosis. Expression of truncated PANX1 (at the putative caspase cleavage site) resulted in a constitutively open channel.PANX1 was also important for the 'selective' plasmamembrane permeability of early apoptotic cells to specific dyes3. Collectively, these data identify PANX1 as a plasma membrane channel mediating the regulated release of find-me signals and selective plasma membrane permeability during apoptosis, and a new mechanism of PANX1 activation by caspases.

Original languageEnglish
Pages (from-to)863-867
Number of pages5
JournalNature
Volume467
Issue number7317
DOIs
StatePublished - Oct 14 2010

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