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Discovery of two opposite signaling roles of PIP3 in determining cell fates for survival and death |
Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal on apoptotic cells. However, Korean researchers at Gachon University College of Medicine discovered externalized phosphatidylinositol phosphates (PIPs) as apoptotic eat-me signals recognized by CD14+ phagocytes using unbiased proteomic analysis. The study appeared in the journal Cell Death and differentiation on January 11, 2022.
Exofacial PIPs on the surfaces of early and late apoptotic cells were observed in patches and blebs using anti-PI(3,4,5)P3antibody,AKT-andPLCδ PH-domains, and CD14 protein. Phagocytosis of apoptotic cells was blocked either by masking exofacial PIPs or CD14 knockout in phagocytes.
The researchers further confirmed that exofacial PIP+ thymocytes increased dramatically after in vivo irradiation and that exofacial PIP+ cells represented more significant populations in tissues of Cd14−/− than WT mice, especially after induction of apoptosis. Their findings revealed exofacial PIPs as previously unknown cell death signals recognized by CD14+ phagocytes.
Prof. Oh said that “ we found that PI(3,4,5)P3 has two opposing signaling roles in determining cell fate; flipped PI(3,4,5)P3 is a cell death signal recognized by phagocytes, whereas inward-facing PI(3,4,5)P3 elicits survival signals for cell growth.” “We also expect that our findings will pave the way for developing new therapeutics in the future, “Prof. Oh said.
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Fig.1. Two opposite signaling roles of PIP3 in determining cell fates for survival and death. PIP3 has two opposing signaling roles in determining cell fate; flipped PIP3 is a cell death signal recognized by phagocytes, whereas inward-facing PIP3 elicits survival signals for cell growth. a) Inward-facing PIP3 elicits survival signals for cell growth. b) Apoptotic cells externalized exofacial PIPs on the surface during cell death. c) Exofacial PIP3 on apoptotic cell surfaces are eat-me signals for recognizing and engulfment by CD14+ macrophages. |
[Reference] Kim, O.-H., Kang, G.-H., Hur, J., Lee, J., Jung, Y., Hong, I.-S., Lee, H., Seo, S.-Y., Lee, D. H., Lee, C. S., Lee, I.-K., Bonner-Weir, S., Lee, J., Park, Y. J., Kim, H., Shoelson, S. E., and Oh, B.-C. (2022) Externalized phosphatidylinositides on apoptotic cells are eat-me signals recognized by CD14. Cell Death & Differentiation. https://doi.org/10.1038/s41418-022-00931-2
[Main Author] Ok-Hee Kim (Gachon University College of Medicine) , Byung-Chul Oh (Gachon University College of Medicine),
* Contact : bcoh@gachon.ac.kr
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