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

Colin D. DeBakker; Lisa B. Haney; Jason M. Kinchen; Cynthia Grimsley; Mingjian Lu; Doris Klingele; Pei Ken Hsu; Bin Kuan Chou; Li Chun Cheng; Anne Blangy; John Sondek; Michael O. Hengartner; Yi Chun Wu; Kodi S. Ravichandran

doi:10.1016/j.cub.2004.12.029

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

Colin D. DeBakker, Lisa B. Haney, Jason M. Kinchen, Cynthia Grimsley, Mingjian Lu, Doris Klingele, Pei Ken Hsu, Bin Kuan Chou, Li Chun Cheng, Anne Blangy, John Sondek, Michael O. Hengartner, Yi Chun Wu, Kodi S. Ravichandran^*

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

176 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2208-2216
Number of pages	9
Journal	Current Biology
Volume	14
Issue number	24
DOIs	https://doi.org/10.1016/j.cub.2004.12.029
State	Published - Dec 29 2004

Funding

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.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

Access to Document

10.1016/j.cub.2004.12.029

Cite this

DeBakker, C. D., Haney, L. B., Kinchen, J. M., Grimsley, C., Lu, M., Klingele, D., Hsu, P. K., Chou, B. K., Cheng, L. C., Blangy, A., Sondek, J., Hengartner, M. O., Wu, Y. C., & Ravichandran, K. S. (2004). Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO. Current Biology, 14(24), 2208-2216. https://doi.org/10.1016/j.cub.2004.12.029

@article{29148903c7e64e4296d26dec4af017a7,

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

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.",

author = "DeBakker, {Colin D.} and Haney, {Lisa B.} and Kinchen, {Jason M.} and Cynthia Grimsley and Mingjian Lu and Doris Klingele and Hsu, {Pei Ken} and Chou, {Bin Kuan} and Cheng, {Li Chun} and Anne Blangy and John Sondek and Hengartner, {Michael O.} and Wu, {Yi Chun} and Ravichandran, {Kodi S.}",

note = "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.). ",

year = "2004",

month = dec,

day = "29",

doi = "10.1016/j.cub.2004.12.029",

language = "English (US)",

volume = "14",

pages = "2208--2216",

journal = "Current Biology",

issn = "0960-9822",

publisher = "Cell Press",

number = "24",

}

DeBakker, CD, Haney, LB, Kinchen, JM, Grimsley, C, Lu, M, Klingele, D, Hsu, PK, Chou, BK, Cheng, LC, Blangy, A, Sondek, J, Hengartner, MO, Wu, YC & Ravichandran, KS 2004, 'Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO', Current Biology, vol. 14, no. 24, pp. 2208-2216. https://doi.org/10.1016/j.cub.2004.12.029

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

UR - http://www.scopus.com/inward/citedby.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 -

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this