Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO.
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.
deBakker
Colin D
CD
Department of Microbiology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
Haney
Lisa B
LB
Kinchen
Jason M
JM
Grimsley
Cynthia
C
Lu
Mingjian
M
Klingele
Doris
D
Hsu
Pei-Ken
PK
Chou
Bin-Kuan
BK
Cheng
Li-Chun
LC
Blangy
Anne
A
Sondek
John
J
Hengartner
Michael O
MO
Wu
Yi-Chun
YC
Ravichandran
Kodi S
KS
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C438369:CED-12 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C099818:DOCK1 protein, human; C465214:ELMO1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C111263:UNC-73 protein, C elegans; C075397:RHOG protein, human; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human; D020558:GTP Phosphohydrolases; C442327:Mig-2 protein, C elegans; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins