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

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.

CYK-4 regulates Rac, but not Rho, during cytokinesis

“…Rac activity was disrupted in two ways: 1) with feeding RNA interference (RNAi) and 2) with a loss-of-function (lof) Rac/CED-10 GTPase mutant (G60R; ced-10(n3246) ; hereafter, Rac(G60R) ; Reddien and Horvitz, 2000 ; Sun et al. , 2012 ; Cabello et al. , 2014 ) that, based on an identical G60R mutation in the closely related KRas, renders the small GTPase stuck in the GTP-bound state but unable to interact with effectors, GAPs, or GEFs ( Gremer et al.…”

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

“…Only in the last years, the combination of suppressor screenings and time‐lapse microscopy analyses has unmasked the existence of negative regulators of Rac dependent engulfment pathways. There is expanding research in the field of the negative regulators of cell clearance aimed at understanding the fundamental mechanisms involved in processes such as neurodegeneration 71, 72, 73. Four independent pathways have been identified as negative regulators of CED‐10/Rac during cell corpse engulfment (Fig.…”

“…PDR‐1/Parkin maintains CED‐10/Rac levels to prevent over‐activated apoptotic cell engulfment or abnormal distal tip cell (DTC) migration 72. In humans, autosomal recessive juvenile Parkinson's disease (AR‐JP) is characterized by parkin mutations 76, a possible mechanism underlying this or other neurodegenerative disease characterized by abnormal CED‐10/Rac degradation could be an acceleration of neurons phagocytosis.…”

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

“…The E3 ubiquitin ligases constitute the third step of the ubiquitination process and have a role in catalyzing the conjugation of ubiquitin to a lysine residue in the target proteins for proteasome-mediated degradation. PDR-1 binds to CED-10 and promotes poly-ubiquitination and subsequent proteasomal degradation of CED-10 (Cabello et al 2014). The GAP protein SRGP-1 binds to CED-10 and promotes CED-10 GTP hydrolysis in vitro, and thereby negatively regulates CED-10 GTPase activity (Neukomm et al 2011a).…”

“…The other two negative regulators in the CED-5-CED-12 signaling pathway, SRGP-1 and PDR-1, reduce the activity and the protein level of CED-10 GTPase, respectively (Neukomm et al 2011a;Cabello et al 2014). PDR-1 is the C. elegans homolog of human E3 ubiquitin ligase Parkin, whose mutations are considered causative of autosomal recessive juvenile parkinsonism (Kitada et al 1998).…”