Apoptotic Cells Trigger Calcium Entry in Phagocytes by Inducing the Orai1-STIM1 Association
Abstract
:1. Introduction
2. Materials and Methods
2.1. Plasmids and Antibodies
2.2. Cell Culture and Transfection
2.3. Mice
2.4. Binding and Internalization Assay
2.5. Measurement of Intracellular Calcium
2.6. Engulfment Assay
2.7. Immunoblotting and Immunoprecipitation
2.8. FRET Analysis for Orai1-STIM1 Association
2.9. SOCE
2.10. Statistical Analysis
3. Results
3.1. Extracellular Calcium Is Required for Internalization of Apoptotic Cells
3.2. Elevation of the Calcium Level in Phagocytes Is Due to Extracellular Calcium Entry during Efferocytosis
3.3. Apoptotic Cell Stimulation Induces the Orai1-STIM1 Interaction in Phagocytes
3.4. Recognition of PS Is Necessary for Induction of the Orai1-STIM1 Association by Apoptotic Cells
3.5. Mertk Is an Upstream Receptor of the PLCγ1-IP3R Axis Activated by Apoptotic Cells
3.6. Mertk Depletion Attenuates the Orai1-STIM1 Association and Calcium Entry during Efferocytosis
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Boada-Romero, E.; Martinez, J.; Heckmann, B.L.; Green, D.R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 2020, 21, 398–414. [Google Scholar] [CrossRef] [PubMed]
- Lauber, K.; Blumenthal, S.G.; Waibel, M.; Wesselborg, S. Clearance of apoptotic cells: Getting rid of the corpses. Mol. Cell 2004, 14, 277–287. [Google Scholar] [CrossRef]
- Fadok, V.A.; Voelker, D.R.; Campbell, P.A.; Cohen, J.J.; Bratton, D.L.; Henson, P.M. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 1992, 148, 2207–2216. [Google Scholar] [PubMed]
- Fadok, V.A.; Bratton, D.L.; Frasch, S.C.; Warner, M.L.; Henson, P.M. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ. 1998, 5, 551–562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Penberthy, K.K.; Ravichandran, K.S. Apoptotic cell recognition receptors and scavenger receptors. Immunol. Rev. 2016, 269, 44–59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, D.; Tosello-Trampont, A.C.; Elliott, M.R.; Lu, M.; Haney, L.B.; Ma, Z.; Klibanov, A.L.; Mandell, J.W.; Ravichandran, K.S. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 2007, 450, 430–434. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miyanishi, M.; Tada, K.; Koike, M.; Uchiyama, Y.; Kitamura, T.; Nagata, S. Identification of Tim4 as a phosphatidylserine receptor. Nature 2007, 450, 435–439. [Google Scholar] [CrossRef] [Green Version]
- Park, S.Y.; Jung, M.Y.; Kim, H.J.; Lee, S.J.; Kim, S.Y.; Lee, B.H.; Kwon, T.H.; Park, R.W.; Kim, I.S. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 2008, 15, 192–201. [Google Scholar] [CrossRef] [Green Version]
- Doran, A.C.; Yurdagul, A., Jr.; Tabas, I. Efferocytosis in health and disease. Nat. Rev. Immunol. 2020, 20, 254–267. [Google Scholar] [CrossRef]
- Lemke, G. Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 2013, 5, a009076. [Google Scholar] [CrossRef] [PubMed]
- Nakanishi, Y.; Shiratsuchi, A. Phagocytic removal of apoptotic spermatogenic cells by Sertoli cells: Mechanisms and consequences. Biol. Pharm. Bull. 2004, 27, 13–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Feng, W.; Yasumura, D.; Matthes, M.T.; LaVail, M.M.; Vollrath, D. Mertk triggers uptake of photoreceptor outer segments during phagocytosis by cultured retinal pigment epithelial cells. J. Biol. Chem. 2002, 277, 17016–17022. [Google Scholar] [CrossRef] [Green Version]
- Young, R.W.; Bok, D. Participation of the retinal pigment epithelium in the rod outer segment renewal process. J. Cell Biol. 1969, 42, 392–403. [Google Scholar] [CrossRef] [PubMed]
- Lemke, G.; Burstyn-Cohen, T. TAM receptors and the clearance of apoptotic cells. Ann. N. Y. Acad. Sci. 2010, 1209, 23–29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scott, R.S.; McMahon, E.J.; Pop, S.M.; Reap, E.A.; Caricchio, R.; Cohen, P.L.; Earp, H.S.; Matsushima, G.K. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001, 411, 207–211. [Google Scholar] [CrossRef] [PubMed]
- Todt, J.C.; Hu, B.; Curtis, J.L. The receptor tyrosine kinase MerTK activates phospholipase C gamma2 during recognition of apoptotic thymocytes by murine macrophages. J. Leukoc. Biol. 2004, 75, 705–713. [Google Scholar] [CrossRef] [PubMed]
- Bagur, R.; Hajnoczky, G. Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling. Mol. Cell 2017, 66, 780–788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Felsenfeld, A.; Rodriguez, M.; Levine, B. New insights in regulation of calcium homeostasis. Curr. Opin. Nephrol. Hypertens. 2013, 22, 371–376. [Google Scholar] [CrossRef]
- Prakriya, M.; Lewis, R.S. Store-Operated Calcium Channels. Physiol. Rev. 2015, 95, 1383–1436. [Google Scholar] [CrossRef] [Green Version]
- Putney, J.W. Forms and functions of store-operated calcium entry mediators, STIM and Orai. Adv. Biol. Regul. 2018, 68, 88–96. [Google Scholar] [CrossRef]
- Yeung, P.S.; Yamashita, M.; Prakriya, M. Molecular basis of allosteric Orai1 channel activation by STIM1. J. Physiol. 2020, 598, 1707–1723. [Google Scholar] [CrossRef]
- Moon, H.; Min, C.; Kim, G.; Kim, D.; Kim, K.; Lee, S.A.; Moon, B.; Yang, S.; Lee, J.; Yang, S.J.; et al. Crbn modulates calcium influx by regulating Orai1 during efferocytosis. Nat. Commun. 2020, 11, 5489. [Google Scholar] [CrossRef]
- Gronski, M.A.; Kinchen, J.M.; Juncadella, I.J.; Franc, N.C.; Ravichandran, K.S. An essential role for calcium flux in phagocytes for apoptotic cell engulfment and the anti-inflammatory response. Cell Death Differ. 2009, 16, 1323–1331. [Google Scholar] [CrossRef] [Green Version]
- Cuttell, L.; Vaughan, A.; Silva, E.; Escaron, C.J.; Lavine, M.; van Goethem, E.; Eid, J.P.; Quirin, M.; Franc, N.C. Undertaker, a Drosophila Junctophilin, links Draper-mediated phagocytosis and calcium homeostasis. Cell 2008, 135, 524–534. [Google Scholar] [CrossRef] [Green Version]
- Itoh, R.E.; Kurokawa, K.; Ohba, Y.; Yoshizaki, H.; Mochizuki, N.; Matsuda, M. Activation of rac and cdc42 video imaged by fluorescent resonance energy transfer-based single-molecule probes in the membrane of living cells. Mol. Cell. Biol. 2002, 22, 6582–6591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Min, C.; Park, J.; Kim, G.; Moon, H.; Lee, S.A.; Kim, D.; Moon, B.; Yang, S.; Lee, J.; Kim, K.; et al. Tim-4 functions as a scavenger receptor for phagocytosis of exogenous particles. Cell Death Dis. 2020, 11, 561. [Google Scholar] [CrossRef] [PubMed]
- Stace, C.L.; Ktistakis, N.T. Phosphatidic acid- and phosphatidylserine-binding proteins. Biochim. Biophys. Acta 2006, 1761, 913–926. [Google Scholar] [CrossRef] [PubMed]
- Santiago, C.; Ballesteros, A.; Martinez-Munoz, L.; Mellado, M.; Kaplan, G.G.; Freeman, G.J.; Casasnovas, J.M. Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 2007, 27, 941–951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nakano, T.; Ishimoto, Y.; Kishino, J.; Umeda, M.; Inoue, K.; Nagata, K.; Ohashi, K.; Mizuno, K.; Arita, H. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J. Biol. Chem. 1997, 272, 29411–29414. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Subramanian, M.; Yurdagul, A., Jr.; Barbosa-Lorenzi, V.C.; Cai, B.; de Juan-Sanz, J.; Ryan, T.A.; Nomura, M.; Maxfield, F.R.; Tabas, I. Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages. Cell 2017, 171, 331–345.e22. [Google Scholar] [CrossRef] [Green Version]
- Saleem, H.; Tovey, S.C.; Molinski, T.F.; Taylor, C.W. Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor. Br. J. Pharmacol. 2014, 171, 3298–3312. [Google Scholar] [CrossRef] [PubMed]
- Schild, A.; Bhardwaj, R.; Wenger, N.; Tscherrig, D.; Kandasamy, P.; Dernic, J.; Baur, R.; Peinelt, C.; Hediger, M.A.; Lochner, M. Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. Int. J. Mol. Sci. 2020, 21, 5604. [Google Scholar] [CrossRef] [PubMed]
- Hanayama, R.; Tanaka, M.; Miwa, K.; Shinohara, A.; Iwamatsu, A.; Nagata, S. Identification of a factor that links apoptotic cells to phagocytes. Nature 2002, 417, 182–187. [Google Scholar] [CrossRef] [PubMed]
- Bhardwaj, R.; Hediger, M.A.; Demaurex, N. Redox modulation of STIM-ORAI signaling. Cell Calcium 2016, 60, 142–152. [Google Scholar] [CrossRef]
- Van der Meer, J.H.; van der Poll, T.; van’t Veer, C. TAM receptors, Gas6, and protein S: Roles in inflammation and hemostasis. Blood 2014, 123, 2460–2469. [Google Scholar] [CrossRef]
- Pozzan, T.; Rizzuto, R.; Volpe, P.; Meldolesi, J. Molecular and cellular physiology of intracellular calcium stores. Physiol. Rev. 1994, 74, 595–636. [Google Scholar] [CrossRef]
- De Maeyer, R.P.H.; van de Merwe, R.C.; Louie, R.; Bracken, O.V.; Devine, O.P.; Goldstein, D.R.; Uddin, M.; Akbar, A.N.; Gilroy, D.W. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat. Immunol. 2020, 21, 615–625. [Google Scholar] [CrossRef]
- Moon, B.; Lee, J.; Lee, S.A.; Min, C.; Moon, H.; Kim, D.; Yang, S.; Moon, H.; Jeon, J.; Joo, Y.E.; et al. Mertk Interacts with Tim-4 to Enhance Tim-4-Mediated Efferocytosis. Cells 2020, 9, 1625. [Google Scholar] [CrossRef]
- Nishi, C.; Toda, S.; Segawa, K.; Nagata, S. Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages. Mol. Cell. Biol. 2014, 34, 1512–1520. [Google Scholar] [CrossRef] [Green Version]
- Toda, S.; Hanayama, R.; Nagata, S. Two-step engulfment of apoptotic cells. Mol. Cell. Biol. 2012, 32, 118–125. [Google Scholar] [CrossRef] [Green Version]
- Lee, J.; Park, B.; Moon, B.; Park, J.; Moon, H.; Kim, K.; Lee, S.A.; Kim, D.; Min, C.; Lee, D.H.; et al. A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin. Cell Death Differ. 2019, 26, 1646–1655. [Google Scholar] [CrossRef] [PubMed]
- Park, D.; Hochreiter-Hufford, A.; Ravichandran, K.S. The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr. Biol. 2009, 19, 346–351. [Google Scholar] [CrossRef] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kim, D.; Moon, H.; Cho, H.; Min, C.; Moon, B.; Yang, S.; Lee, J.; Lee, S.-A.; Park, H.; Lee, D.-H.; et al. Apoptotic Cells Trigger Calcium Entry in Phagocytes by Inducing the Orai1-STIM1 Association. Cells 2021, 10, 2702. https://doi.org/10.3390/cells10102702
Kim D, Moon H, Cho H, Min C, Moon B, Yang S, Lee J, Lee S-A, Park H, Lee D-H, et al. Apoptotic Cells Trigger Calcium Entry in Phagocytes by Inducing the Orai1-STIM1 Association. Cells. 2021; 10(10):2702. https://doi.org/10.3390/cells10102702
Chicago/Turabian StyleKim, Deokhwan, Hyunji Moon, Hyeokjin Cho, Chanhyuk Min, Byeongjin Moon, Susumin Yang, Juyeon Lee, Sang-Ah Lee, Hyunjin Park, Dae-Hee Lee, and et al. 2021. "Apoptotic Cells Trigger Calcium Entry in Phagocytes by Inducing the Orai1-STIM1 Association" Cells 10, no. 10: 2702. https://doi.org/10.3390/cells10102702