Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO

Curr Biol. 2004 Dec 29;14(24):2208-16. doi: 10.1016/j.cub.2004.12.029.

Abstract

Background: Phagocytosis of cells undergoing apoptosis is essential during development, cellular turnover, and wound healing. Failure to promptly clear apoptotic cells has been linked to autoimmune disorders. C. elegans CED-12 and mammalian ELMO are evolutionarily conserved scaffolding proteins that play a critical role in engulfment from worm to human. ELMO functions together with Dock180 (a guanine nucleotide exchange factor for Rac) to mediate Rac-dependent cytoskeletal reorganization during engulfment and cell migration. However, the components upstream of ELMO and Dock180 during engulfment remain elusive.

Results: Here, we define a conserved signaling module involving the small GTPase RhoG and its exchange factor TRIO, which functions upstream of ELMO/Dock180/Rac during engulfment. Complementary studies in C. elegans show that MIG-2 (which we identify as the homolog of mammalian RhoG) and UNC-73 (the TRIO homolog) also regulate corpse clearance in vivo, upstream of CED-12. At the molecular level, we identify a novel set of evolutionarily conserved Armadillo (ARM) repeats within CED-12/ELMO that mediate an interaction with activated MIG-2/RhoG; this, in turn, promotes Dock180-mediated Rac activation and cytoskeletal reorganization.

Conclusions: The combination of in vitro and in vivo studies presented here identify two evolutionarily conserved players in engulfment, TRIO/UNC73 and RhoG/MIG-2, and the TRIO --> RhoG signaling module is linked by ELMO/CED-12 to Dock180-dependent Rac activation during engulfment. This work also identifies ARM repeats within CED-12/ELMO and their role in linking RhoG and Rac, two GTPases that function in tandem during engulfment.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / metabolism*
  • GTP Phosphohydrolases / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Nerve Tissue Proteins / metabolism*
  • Phagocytosis / physiology*
  • Phosphoproteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repetitive Sequences, Nucleic Acid / genetics
  • Signal Transduction / physiology*
  • rac GTP-Binding Proteins / metabolism*
  • rho GTP-Binding Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • CED-12 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DOCK1 protein, human
  • ELMO1 protein, human
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • Phosphoproteins
  • UNC-73 protein, C elegans
  • RHOG protein, human
  • Protein-Serine-Threonine Kinases
  • TRIO protein, human
  • GTP Phosphohydrolases
  • Mig-2 protein, C elegans
  • rac GTP-Binding Proteins
  • rho GTP-Binding Proteins