Integrin α PAT-2/CDC-42 Signaling Is Required for Muscle-Mediated Clearance of Apoptotic Cells in Caenorhabditis elegans

Abstract

Clearance of apoptotic cells by engulfment plays an important role in the homeostasis and development of multicellular organisms. Despite the fact that the recognition of apoptotic cells by engulfment receptors is critical in inducing the engulfment process, the molecular mechanisms are still poorly understood. Here, we characterize a novel cell corpse engulfment pathway mediated by the integrin α subunit PAT-2 in Caenorhabditis elegans and show that it specifically functions in muscle-mediated engulfment during embryogenesis. Inactivation of pat-2 results in a defect in apoptotic cell internalization. The PAT-2 extracellular region binds to the surface of apoptotic cells in vivo, and the intracellular region may mediate signaling for engulfment. We identify essential roles of small GTPase CDC-42 and its activator UIG-1, a guanine-nucleotide exchange factor, in PAT-2–mediated cell corpse removal. PAT-2 and CDC-42 both function in muscle cells for apoptotic cell removal and are co-localized in growing muscle pseudopods around apoptotic cells. Our data suggest that PAT-2 functions through UIG-1 for CDC-42 activation, which in turn leads to cytoskeletal rearrangement and apoptotic cell internalization by muscle cells. Moreover, in contrast to PAT-2, the other integrin α subunit INA-1 and the engulfment receptor CED-1, which signal through the conserved signaling molecules CED-5 (DOCK180)/CED-12 (ELMO) or CED-6 (GULP) respectively, preferentially act in epithelial cells to mediate cell corpse removal during mid-embryogenesis. Our results show that different engulfing cells utilize distinct repertoires of receptors for engulfment at the whole organism level.

Signaling by the Engulfment Receptor Draper: A Screen in Drosophila melanogaster Implicates Cytoskeletal Regulators, Jun N-Terminal Kinase, and Yorkie

“…Evidence suggests that Plx interacts with integrins (Zhang et al 1996). Integrins are receptors for apoptotic corpses in mammals and in the C. elegans Ced2, 5, 10, 12 engulfment pathway (D'mello and Birge 2010; Hsieh et al 2012), but no apoptotic role for Drosophila integrins is known. Plx is homologous to the human TBC1D1 and TBC1D4 proteins and, as such, might function as a RabGAP (Laflamme et al 2012).…”

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

“…Cell types such as hypodermal cells (which constitute the external epithelium), muscle cells, and intestinal cells have been shown to function as engulfing cells to remove somatic apoptotic cells (Robertson and Thomson 1982;Sulston et al 1983;Zhou et al 2001b;Hsieh et al 2012). Germ cell corpses are specifically engulfed by gonadal sheath cells, which wrap around the germ line syncytium (Gumienny et al 2001).…”

“…For example, the recruitment of EPN-1 and CHC-1 to phagocytic cups during cell corpse engulfment is independent of CED-5, CED-12, or CED-10; suggesting that the remodeling of actin regulated by the CED-1-EPN-1-clathrin pathway may not require CED-10 (Shen et al 2013). Instead, ced-10 and cdc-42 have been placed in two separate pathways, both of which act in parallel to that of ced-1, ced-6, and ced-7 (see below) Reddien and Horvitz 2000;Yu et al 2006;Hsieh et al 2012;Shen et al 2013). …”

“…The PAT-2 and PAT-3 pathway: The third engulfment pathway is mediated by the integrin PAT-2/PAT-3 (Hsieh et al 2012;Neukomm et al 2014). The integrin a subunit PAT-2, like the other integrin a subunit INA-1, clusters on the surface of apoptotic cells (Hsu and Wu 2010;Hsieh et al 2012), but whether PAT-2 may bind to exposed PS is not known.…”

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

“…Anderson et al proposed that there might be other yet unidentified molecular pathways that activate the Wave Regulatory Complex (WRC) in parallel to ced‐10 68. In fact, integrins PAT‐2/PAT‐3 function in muscle cells, recognizing exposed PS and signaling through UNC‐112/FERMT2 and UIG‐1, a GEF specific for the small GTPase CDC‐42 (cell division control protein‐42) 69. Activated CDC‐42 is then recruited to the plasma membrane surrounding apoptotic corpses 70.…”