TY - JOUR
T1 - Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO
AU - DeBakker, Colin D.
AU - Haney, Lisa B.
AU - Kinchen, Jason M.
AU - Grimsley, Cynthia
AU - Lu, Mingjian
AU - Klingele, Doris
AU - Hsu, Pei Ken
AU - Chou, Bin Kuan
AU - Cheng, Li Chun
AU - Blangy, Anne
AU - Sondek, John
AU - Hengartner, Michael O.
AU - Wu, Yi Chun
AU - Ravichandran, Kodi S.
N1 - Funding Information:
We are grateful to Krister Wennerberg for HA-tagged RhoG plasmids, Ann Debant for GFP-tagged TRIO plasmids, Michiyuki Matsuda for the original His-Dock180 plasmid, and Ian Macara for the His-tagged bacterially produced Rac. We thank members of the Ravichandran, Hengartner, and Sondek laboratories for helpful suggestions during this work. This work was supported by National Institutes of Health grant GM-64709 (to K.S.R.), an Infectious Diseases Training grant from the National Institutes of Health (C.G.), grants from the National Science Council and National Health Research Institutes (to Y.-C.W.), and grants from the Swiss National Science Foundation, The Ernst Hadorn Foundation, and the European Union (FP5 project APOCLEAR) (to M.O.H.).
PY - 2004/12/29
Y1 - 2004/12/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=19944376460&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2004.12.029
DO - 10.1016/j.cub.2004.12.029
M3 - Article
C2 - 15620647
AN - SCOPUS:19944376460
SN - 0960-9822
VL - 14
SP - 2208
EP - 2216
JO - Current Biology
JF - Current Biology
IS - 24
ER -