Pannexin 1 channels mediate ‘find–me’ signal release and membrane permeability during apoptosis

By Faraaz B. Chekeni, Michael R. Elliott, Joanna K. Sandilos, S. Walk, J. Kinchen, E. Lazarowski, A. Armstrong, S. Penuela, D. Laird, G. Salvesen and 3 more. Nature, 2010

1,105 citations recorded by the source corpus.

Apoptotic cells release ‘find-me’ signals at the earliest stages of death to recruit phagocytes. The nucleotides ATP and UTP represent 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’ plasma membrane permeability of early apoptotic cells to specific dyes. 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.

Subfields: Immunology, Obstetrics and Gynecology, Physiology

View Paper: https://www.semanticscholar.org/paper/8459138c34e192f892d993ff9a329b11775ee319

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Citations in the corpus

Programmed Cell Death in Animal Development and Disease (2011, neutral): “PANX1 is a target of effector caspase-3 and -7, in which a specific caspase cleavage site is essential for PANX1 function in mediating release of ‘‘find me’’ signals during apoptosis (Chekeni et al., 2010).”
Ion Channels in Innate and Adaptive Immunity (2015, background): “Panx1 is upregulated in human neutrophils by various stimuli including fMLP, IL-8, C5a, and leukotrienes, and it mediates ATP release from these cells (66).”
Immunogenic cell death and DAMPs in cancer therapy (2012, background): “These authors showed that a recombinant N-terminal fragment of CRT (39-272) is a potent inducer of activation and maturation of B cells and macrophages and can trigger Ig class switching in B cells without T cell help in vitro and in vivo72.”
Consensus guidelines for the detection of immunogenic cell death (2014, background): “The ICD-associated release of ATP proceeds through a complex mechanism that involves (1) the apparent relocalization of vesicular ATP stores from lysosomes to autolysosomes; (2) the redistribution of lysosomal-associated membrane protein 1 (LAMP1) to the plasma membrane; (3) Rho-associated, coiledco”
A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death (2012, positive): “…associated with mechanical/osmotic strain (Nandigama et al , 2006), cells in early apoptotic stages, during which caspases are active (Elliott et al , 2009; Chekeni et al , 2010) or in mid apoptotic stages, coincident with nuclear fragmentation (Ghiringhelli et al , 2009; Martins et al , 2009).”
Focus on Extracellular Vesicles: Introducing the Next Small Big Thing (2016, background): “This formation of apoptopodia (and ABs) in T lymphocytes is negatively regulated by the caspase-activated pannexin 1 (PANX1) channel [122].”