Polarization of the epithelial layer and apical localization of integrins are required for engulfment of apoptotic cells

Meehan, Tracy L.; Kleinsorge, Sarah E.; Timmons, Allison K.; Taylor, Jeffrey D.; McCall, Kimberly

doi:10.1242/dmm.021998

Cited by 16 publications

(38 citation statements)

References 54 publications

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“…The level of integrin ␤ remained unchanged in phagocytes after the stimulation. However, we speculate that stimulated phagocytes acquire an increased level of a heterodimer of the integrin subunits ␣PS3 and ␤ because the surface expression of integrins appears to depend on the level of ␣-subunits, as exemplified by integrin ␣ 1 -␤ 1 in human osteosarcoma cells (29) and integrin ␣PS3-␤PS in the epithelial follicle cells of Drosophila ovaries (30).…”

Section: Increase In the Levels Of Phagocytic Activity And Engulfmentmentioning

confidence: 99%

Signaling pathway for phagocyte priming upon encounter with apoptotic cells

Nonaka¹,

Ando²,

Kanetani³

et al. 2017

Journal of Biological Chemistry

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The phagocytic elimination of cells undergoing apoptosis is an evolutionarily conserved innate immune mechanism for eliminating unnecessary cells. Previous studies showed an increase in the level of engulfment receptors in phagocytes after the phagocytosis of apoptotic cells, which leads to the enhancement of their phagocytic activity. However, precise mechanisms underlying this phenomenon require further clarification. We found that the pre-incubation of a phagocyte cell line with the fragments of apoptotic cells enhanced the subsequent phagocytosis of apoptotic cells, accompanied by an augmented expression of the engulfment receptors Draper and integrin αPS3. The DNA-binding activity of the transcription repressor Tailless was transiently raised in those phagocytes, depending on two partially overlapping signal-transduction pathways for the induction of phagocytosis as well as the occurrence of engulfment. The RNAi knockdown of in phagocytes abrogated the enhancement of both phagocytosis and engulfment receptor expression. Furthermore, the hemocyte-specific RNAi of reduced apoptotic cell clearance in embryos. Taken together, we propose the following mechanism for the activation of phagocytes after an encounter with apoptotic cells: two partially overlapping signal-transduction pathways for phagocytosis are initiated; transcription repressor Tailless is activated; expression of engulfment receptors is stimulated; and phagocytic activity is enhanced. This phenomenon most likely ensures the phagocytic elimination of apoptotic cells by stimulated phagocytes and is thus considered as a mechanism to prime phagocytes in innate immunity.

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Section: Increase In the Levels Of Phagocytic Activity And Engulfmentmentioning

confidence: 99%

Signaling pathway for phagocyte priming upon encounter with apoptotic cells

Nonaka¹,

Ando²,

Kanetani³

et al. 2017

Journal of Biological Chemistry

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“…A strong candidate is integrins, which have been shown to function during engulfment in C. elegans, mammals, and recently flies. 37 In flies, there are 7 different integrin subunits that can form different combinations of a/ ß heterodimers. Knockdown of most of the integrin subunits did not affect programmed cell death in late oogenesis.…”

Section: Engulfment Receptors Integrins and Draper Function In Parallelmentioning

confidence: 99%

“…32,37 The phagosomes are then processed through the canonical phagosome maturation pathway. 40 Phagosome formation and processing during starvation-induced cell death in mid-oogenesis are dependent on the phagocytosis genes draper, Ced-12, integrins, and the JNK pathway.…”

Section: Future Perspectivesmentioning

confidence: 99%

Control of non-apoptotic nurse cell death by engulfment genes in Drosophila

Timmons

Mondragon

Meehan

et al. 2016

Fly

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Programmed cell death occurs as a normal part of oocyte development in Drosophila. For each egg that is formed, 15 germline-derived nurse cells transfer their cytoplasmic contents into the oocyte and die. Disruption of apoptosis or autophagy only partially inhibits the death of the nurse cells, indicating that other mechanisms significantly contribute to nurse cell death. Recently, we demonstrated that the surrounding stretch follicle cells non-autonomously promote nurse cell death during late oogenesis and that phagocytosis genes including draper, ced-12, and the JNK pathway are crucial for this process. When phagocytosis genes are inhibited in the follicle cells, events specifically associated with death of the nurse cells are impaired. Death of the nurse cells is not completely blocked in draper mutants, suggesting that other engulfment receptors are involved. Indeed, we found that the integrin subunit, aPS3, is enriched on stretch follicle cells during late oogenesis and is required for elimination of the nurse cells. Moreover, double mutant analysis revealed that integrins act in parallel to draper. Death of nurse cells in the Drosophila ovary is a unique example of programmed cell death that is both non-apoptotic and non-cell autonomously controlled.

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“…In Drosophila , Rac1 is activated by Ced-5/Ced-12, but it is not known what acts upstream of Ced-5/Ced-12 [ 9 , 10 ]. In Drosophila hemocytes, integrins have recently been shown to be required for engulfment [ 11 – 14 ] and Draper has been shown to work in parallel to integrins in these cells [ 11 ]. Ced-12 has been shown to activate Rac1 in conjunction with another GEF, DRK/DOS/SOS, both acting downstream of Draper in phagocytic glia [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Components of the Engulfment Machinery Have Distinct Roles in Corpse Processing

et al. 2016

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Billions of cells die in our bodies on a daily basis and are engulfed by phagocytes. Engulfment, or phagocytosis, can be broken down into five basic steps: attraction of the phagocyte, recognition of the dying cell, internalization, phagosome maturation, and acidification. In this study, we focus on the last two steps, which can collectively be considered corpse processing, in which the engulfed material is degraded. We use the Drosophila ovarian follicle cells as a model for engulfment of apoptotic cells by epithelial cells. We show that engulfed material is processed using the canonical corpse processing pathway involving the small GTPases Rab5 and Rab7. The phagocytic receptor Draper is present on the phagocytic cup and on nascent, phosphatidylinositol 3-phosphate (PI(3)P)- and Rab7-positive phagosomes, whereas integrins are maintained on the cell surface during engulfment. Due to the difference in subcellular localization, we investigated the role of Draper, integrins, and downstream signaling components in corpse processing. We found that some proteins were required for internalization only, while others had defects in corpse processing as well. This suggests that several of the core engulfment proteins are required for distinct steps of engulfment. We also performed double mutant analysis and found that combined loss of draper and αPS3 still resulted in a small number of engulfed vesicles. Therefore, we investigated another known engulfment receptor, Crq. We found that loss of all three receptors did not inhibit engulfment any further, suggesting that Crq does not play a role in engulfment by the follicle cells. A more complete understanding of how the engulfment and corpse processing machinery interact may enable better understanding and treatment of diseases associated with defects in engulfment by epithelial cells.

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Polarization of the epithelial layer and apical localization of integrins are required for engulfment of apoptotic cells

Cited by 16 publications

References 54 publications

Signaling pathway for phagocyte priming upon encounter with apoptotic cells

Signaling pathway for phagocyte priming upon encounter with apoptotic cells

Control of non-apoptotic nurse cell death by engulfment genes in Drosophila

Components of the Engulfment Machinery Have Distinct Roles in Corpse Processing

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