Two Alternative Mechanisms That Regulate the Presentation of Apoptotic Cell Engulfment Signal inCaenorhabditis elegans

Abstract

Phosphatidylserine exposed on the surface of apoptotic mammalian cells is considered an "eat-me" signal that attracts phagocytes. The generality of using phosphatidylserine as a clearance signal for apoptotic cells in animals and the regulation of this event remain uncertain. Using ectopically expressed mouse MFG-E8, a secreted phosphatidylserinebinding protein, we detected specific exposure of phosphatidylserine on the surface of apoptotic cells in Caenorhabditis elegans. Masking the surface phosphatidylserine inhibits apoptotic cell engulfment. CED-7, an ATP-binding cassette (ABC) transporter, is necessary for the efficient exposure of phosphatidylserine on apoptotic somatic cells, and for the recognition of these cells by phagocytic receptor CED-1. Alternatively, phosphatidylserine exposure on apoptotic germ cells is not CED-7 dependent, but instead requires phospholipid scramblase PLSC-1, a homologue of mammalian phospholipid scramblases. Moreover, deleting plsc-1 results in the accumulation of apoptotic germ cells but not apoptotic somatic cells. These observations suggest that phosphatidylserine might be recognized by CED-1 and act as a conserved eat-me signal from nematodes to mammals. Furthermore, the two different biochemical activities used in somatic cells (ABC transporter) and germ cells (phospholipid scramblase) suggest an increased complexity in the regulation of phosphatidylserine presentation in response to apoptotic signals in different tissues and during different developmental stages.

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

“…PS, which is normally restricted to the inner leaflet of the plasma membrane, is externalized during apoptosis and serves as an eat me signal to trigger phagocytosis (Fadok et al 1992a;Martin et al 1995;Fadok et al 1998). PS exposure on the surface of apoptotic cells in C. elegans has been shown to be a conserved apoptotic event and is important for removal of apoptotic cells (Venegas and Zhou 2007;Wang et al 2007;Zullig et al 2007). Interestingly, both WAH-1 and its human homolog AIF, the proapoptotic factors critical for nuclear DNA degradation, are also involved in promoting PS externalization in apoptotic cells (Susin et al 1999;Wang et al 2007).…”

“…Externalization of PS on the cell surface is a hallmark of apoptosis; exposed PS is a conserved eat me signal that triggers phagocytosis in many organisms, including C. elegans (Fadeel and Xue 2009). Using a secreted PS-binding protein GFP fusion such as the Annexin V::GFP fusion (sAnxV::GFP), the MFG-E8::GFP, or the secreted GFP::lactadherin fusion (sGFP::Lact C1C2 ) as a PS sensor; exposed PS is detected on the surface of apoptotic cells in C. elegans (Fadok et al 2001;Venegas and Zhou 2007;Wang et al 2007;Zullig et al 2007;Mapes et al 2012;Zhang et al 2012).…”

“…Two bidirectional phospholipid scramblases, SCRM-1 and SCRM-3, have been implicated in PS exposure on the surface of apoptotic cells (Venegas and Zhou 2007;Wang et al 2007). Loss of scrm-1 or scrm-3 (also called plsc-1), which encodes two of the eight C. elegans phospholipid scramblases, results in reduced PS exposure on the surface of apoptotic germ cells and a defect in the removal of apoptotic cells (Venegas and Zhou 2007;Wang et al 2007;Hsu and Wu 2010).…”

“…Loss of scrm-1 or scrm-3 (also called plsc-1), which encodes two of the eight C. elegans phospholipid scramblases, results in reduced PS exposure on the surface of apoptotic germ cells and a defect in the removal of apoptotic cells (Venegas and Zhou 2007;Wang et al 2007;Hsu and Wu 2010). Loss of scrm-1 or scrm-3 only partially reduces PS exposure in apoptotic cells, suggesting that additional factors or lipid transporters are involved in mediating PS exposure in apoptotic cells.…”

The Active Role of Corpse Engulfment Pathways During Cell Competition

“…Phosphatidylserine exposure on the outer membrane leaflet is a conserved feature of apoptosis, and recognized by mammalian macrophage and during corpse engulfment in C. elegans. [16][17][18][19] The so-called psr gene was identified by expression-cloning the target of an engulfment-blocking antibody, 20 but is now thought to encode a nuclear protein, and recent studies have convincingly demonstrated that it is not required for corpse engulfment by either mouse fibroblasts or Drosophila hemocytes. 21,22 Meanwhile, other mechanisms of recognizing phosphatidylserine have been uncovered in mammals.…”