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

Department of Microbiology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
Current Biology (Impact Factor: 9.57). 01/2005; 14(24):2208-16. DOI: 10.1016/j.cub.2004.12.029
Source: PubMed


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.
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.
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.

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    • "Although the ubiquitous, archetype of the family, DOCK180, has been shown to be sufficient to act as a GEF for Rac1 both in vitro and in cellulo [7] [8], DOCK180 cooperates with ELMO for an efficient Rac1 signaling in vivo [4,9– 12]. Thus, ELMO1 has been shown (i) to relieve the auto-inhibition of DOCK180 through direct binding, (ii) to trigger DOCK180 stabilization of the nucleotide free form of Rac1 [10] [13], and (iii) to facilitate the recruitment of DOCK180 to the membrane [14] [15]. "
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    • "We have not identified the upstream signals that control RacGEF activation in this process, though a role for integrins has been reported (Lucanic and Cheng 2008). Our data also suggest that MIG-2/RhoG, which activates the Dock/ELMO atypical RacGEF complex in human and C. elegans cell corpse engulfment (deBakker et al. 2004), does not activate the CED-2/5/12 Dock/ELMO RacGEF complex in DTC migration. We place MIG-2/RhoG in parallel to the Paks and CED-10/Rac because of the apparent mutant additivity. "
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    • "It is already well known that members of the Rho family of small GTPases play pivotal roles in the regulation of cell morphology, migration , proliferation, and survival. Among them, RhoG is a key upstream regulator of another Rho family member Rac to induce diverse cellular functions, including promotion of cell migration, neurite outgrowth in neuronal cells, and stimulation of phagocytosis [5] [6] [7]. ELMO is an effector for RhoG that mediates activation of Rac through the interaction with Rac GEF Dock180 or Dock4. "
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