PDR-1/hParkin negatively regulates the phagocytosis of apoptotic cell corpses in Caenorhabditis elegans

J Cabello,J Sämann,A Pujol,E Dalfo,I Ferrer,B Schulze,J M Lizcano,R Baumeister,E Gómez-Orte,I Büssing,T Erazo,A Coppa

doi:10.1038/cddis.2014.57

Abstract

Apoptotic cell death is an integral part of cell turnover in many tissues, and proper corpse clearance is vital to maintaining tissue homeostasis in all multicellular organisms. Even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. In Caenorhabditis elegans, two parallel and partly redundant conserved pathways act in cell corpse engulfment. The pathway for cytoskeletal rearrangement requires the small GTPase CED-10 Rac1 acting for an efficient surround of the dead cell. The CED-10 Rac pathway is also required for the proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. Parkin, the mammalian homolog of the C. elegans PDR-1, interacts with Rac1 in aged human brain and it is also implicated with actin dynamics and cytoskeletal rearrangements in Parkinsons's disease, suggesting that it might act on engulfment. Our genetic and biochemical studies indicate that PDR-1 inhibits apoptotic cell engulfment and DTC migration by ubiquitylating CED-10 for degradation.

Highlights

Studies in the nematode Caenorhabditis elegans (C. elegans) suggested that apoptotic cells are recognized and cleared before they are ‘fully dead’
The nematode C. elegans was used as the model to study the regulation of ced-10 by pdr-1 because of the simplicity of C. elegans as an animal model to study genetic interactions, and because mechanisms controlling the engulfment in C. elegans are conserved in metazoa.[4]
To test first whether pdr-1 had a role in engulfment, the number of unengulfed cell corpses was counted in the heads of first larval stage (L1) animals, harboring mutations in pdr-1 and ced-10

Summary

Introduction

Studies in the nematode Caenorhabditis elegans (C. elegans) suggested that apoptotic cells are recognized and cleared before they are ‘fully dead’.3,4. Two evolutionary conserved and partially redundant signaling pathways act together in the clearance of cell corpses during development and in the germline in C. elegans: (a) CED-2, CED-5 and CED-12 and (b) CED-1, CED-6 and CED-7, both converging in the activation of the small GTPase CED-10 (Rac[1] in mammals), which, eventually, promote cytoskeletal reorganization and cell corpse engulfment.[5,6] In addition, two independent signaling pathways have been described very recently: the one acting through the ABI-1 tyrosine kinase and the other being regulated by the SLI-1 ligase.[7,8] the redundancy of these new pathways to the canonical engulfment branches still cannot be discarded. GTP-bound Rac has an evolutionary conserved positive effect on engulfment, and Rac activation at sites of apoptotic cell recognition subsequently leads to cytoskeletal rearrangement.[9,10] Once Rac[1] is activated, it is ubiquitylated for targeting to proteasomal degradation.[11,12] The specific E3 ubiquitin ligase regulating Rac[1] degradation in the scenario of the engulfment remains elusive. Parkin encodes a protein with E3 ligase activity whose loss of function is considered causative of autosomal

Methods

Results

Conclusion