SLI-1 Cbl Inhibits the Engulfment of Apoptotic Cells in C. elegans through a Ligase-Independent Function

Courtney Anderson,Emma Sawin,Shan Zhou,Michael E Hurwitz,H Robert Horvitz

doi:10.1371/journal.pgen.1003115

Abstract

The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway, which includes the small GTPase CED-10 Rac and the cytoskeletal regulator ABI-1, acts to rearrange the cytoskeleton of the engulfing cell. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The second pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Cbl, the mammalian homolog of the C. elegans E3 ubiquitin ligase and adaptor protein SLI-1, interacts with Rac and Abi2 and modulates the actin cytoskeleton, suggesting it might act in engulfment. Our genetic studies indicate that SLI-1 inhibits apoptotic cell engulfment and DTC migration independently of the CED-10 Rac and CED-1 pathways. We found that the RING finger domain of SLI-1 is not essential to rescue the effects of SLI-1 deletion on cell migration, suggesting that its role in this process is ubiquitin ligase-independent. We propose that SLI-1 opposes the engulfment of apoptotic cells via a previously unidentified pathway.

Highlights

The engulfment of apoptotic cells requires at least two processes to occur in the engulfing cell at the interface with the dying cell
The c-Cbl proto-oncogene interacts with Rac and Abi2 and has been shown to regulate the actin cytoskeleton, so we tested whether the C. elegans homolog of Cbl, SLI-1, regulates engulfment and cell migration
Most of the known functions of Cbl proteins require that domain, but we found that SLI-1 did not require it to block engulfment and cell migration

Summary

Introduction

The engulfment of apoptotic cells requires at least two processes to occur in the engulfing cell at the interface with the dying cell. Actin cytoskeletal elements need to be reorganized and membrane needs to be recruited. Together, these two processes result in the engulfing cell surrounding the dying cell. In the pathway for membrane recruitment, which we refer to as the CED-1 pathway, four proteins have been identified, CED-7, CED-1, CED-6 and DYN-1 (Figure 1) [1]. These proteins activate DYN-1, a C. elegans dynamin homolog [2], which might recruit membrane for engulfment; in mammalian cells dynamin promotes extension of lamellipodial membrane protrusions [3]

Methods

Results

Discussion

Conclusion