Phagocytic Receptor CED-1 Initiates a Signaling Pathway for Degrading Engulfed Apoptotic Cells

Xiaomeng Yu,Zheng Zhou,Nan Lu,Kai L Simons

doi:10.1371/journal.pbio.0060061

Abstract

Apoptotic cells in animals are engulfed by phagocytic cells and subsequently degraded inside phagosomes. To study the mechanisms controlling the degradation of apoptotic cells, we developed time-lapse imaging protocols in developing Caenorhabditis elegans embryos and established the temporal order of multiple events during engulfment and phagosome maturation. These include sequential enrichment on phagocytic membranes of phagocytic receptor cell death abnormal 1 (CED-1), large GTPase dynamin (DYN-1), phosphatidylinositol 3-phosphate (PI(3)P), and the small GTPase RAB-7, as well as the incorporation of endosomes and lysosomes to phagosomes. Two parallel genetic pathways are known to control the engulfment of apoptotic cells in C. elegans. We found that null mutations in each pathway not only delay or block engulfment, but also delay the degradation of engulfed apoptotic cells. One of the pathways, composed of CED-1, the adaptor protein CED-6, and DYN-1, controls the rate of enrichment of PI(3)P and RAB-7 on phagosomal surfaces and the formation of phagolysosomes. We further identified an essential role of RAB-7 in promoting the recruitment and fusion of lysosomes to phagosomes. We propose that RAB-7 functions as a downstream effector of the CED-1 pathway to mediate phagolysosome formation. Our work suggests that phagocytic receptors, which were thought to act specifically in initiating engulfment, also control phagosome maturation through the sequential activation of multiple effectors such as dynamin, PI(3)P, and Rab GTPases.

Highlights

An engulfing cell recognizes an apoptotic cell through phagocytic receptor(s) and extends thin pseudopods around it to generate a phagocytic cup
Cells undergoing programmed cell death, or apoptosis, within an animal are swiftly engulfed by phagocytes and degraded inside phagosomes, vesicles in which the apoptotic cell is bounded by the engulfing cell’s membrane
We studied the degradation of apoptotic cells during the development of the nematode Caenorhabditis elegans

Summary

Introduction

An engulfing cell recognizes an apoptotic cell through phagocytic receptor(s) and extends thin pseudopods around it to generate a phagocytic cup. The fusion of growing pseudopods and scission of a vacuole containing the apoptotic cell from the plasmalemma generate a phagosome inside the host cell (Figure 1A) [1]. The swift engulfment (phagocytosis) and subsequent degradation of apoptotic cells inside phagosomes eliminate dying cells before they release any potentially harmful contents, and actively prevent tissue injury, inflammatory responses, and autoimmune diseases [2]. Inefficient degradation of the components of engulfed apoptotic cells, such as nuclear DNA, similar to inefficient engulfment, results in severe inflammatory and autoimmune responses [3,4]. The maturation of phagosomes containing apoptotic cells, by contrast, is less characterized, and may display distinct mechanistic features. Macrophages that internalize foreign pathogens secrete proinflammatory cytokines that induce inflammatory responses, whereas those engulfing apoptotic cells secrete anti-inflammatory cytokines, indicating that the same type of phagocytes elicit different responses to different phagocytic targets [2,7]

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Discussion

Conclusion