Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis
Open accessAbstract
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.
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In ICD, ATP release occurs downstream of caspase activation and involves autolysosomal ATP accumulation, LAMP1 relocalization, ROCK1-dependent blebbing, and PANX1 opening.
“In the context of ICD, ATP is released through a cascade of events occurring downstream of caspase activation and involving: (1) the autophagy-dependent accumulation of ATP within autolysosomes (the organelles forming by the fusion of autophagosomes or amphisomes with lysosomes), (2) the relocalization of lysosomal-associated membrane protein 1 (LAMP1) to the plasma membrane, (3) ROCK1-dependent”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [899]
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“a “find me” signal necessary for macropha e recruitment [96].”
BackgroundImmunoregulation through extracellular nucleotides
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- Authors
- Chekeni, F. B., Elliott, M. R., Sandilos, J. K., Walk, S. F., Kinchen, J. M., Lazarowski, E. R., Armstrong, A. J., Penuela, S., Laird, D. W., Salvesen, G. S., Isakson, B. E., Bayliss, D. A., & Ravichandran, K. S.
- Affiliations
- University of Virginia (US)
- University of North Carolina at Chapel Hill (US)
- Western University (CA)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Ravichandran, Kodi S.
- ORCID
- Venue
- Nature
- Published
- 2010-10
- Volume
- 467
- Issue
- 7317
- Pages
- 863-867
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3006164
- OpenAlex
- W1971084572
- Cited by
- 1,120
- References
- 27
- Citations by year
- 2026: 54 · 2025: 70 · 2024: 65 · 2023: 61 · 2022: 87 · 2021: 91 · 2020: 75 · 2019: 53 · 2018: 70 · 2017: 78 · 2016: 71 · 2015: 77 · 2014: 81 · 2013: 61 · 2012: 78
- FWCI
- 40.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (F30HL096400)
- National Institute of Allergy and Infectious Diseases (T32AI055432, T32AI007496)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK067629)
- National Institute of Neurological Disorders and Stroke (R01NS033583)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- pannexin 1, find-me signals, apoptosis, ATP release, caspase activation, caspase-3, caspase-7, plasma membrane permeability, phagocyte recruitment, purinergic signaling
- MeSH terms
- Adenosine Triphosphate, Carbenoxolone, Cell Membrane Permeability, Chemotaxis, Electric Conductivity, Humans, Nerve Tissue Proteins, Phagocytes, Phagocytosis, Uridine Triphosphate, Apoptosis, Connexins, Patch-Clamp Techniques, Jurkat Cells, Caspase 3, Caspase 7
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