Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans
L J Neukomm1, S Zeng2, A P Frei1
1Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Abstract:
The rapid clearance of dying cells is important for the well-being of multicellular organisms. In C. elegans, cell corpse removal is mainly mediated by three parallel engulfment signaling cascades. These pathways include two small GTPases, MIG-2/RhoG and CED-10/Rac1. Here we present the identification and characterization of CDC-42 as a third GTPase involved in the regulation of cell corpse clearance. Genetic analyses performed by both loss of cdc-42 function and cdc-42 overexpression place cdc-42 in parallel to the ced-2/5/12 signaling module, in parallel to or upstream of the ced-10 module, and downstream of the ced-1/6/7 module. CDC-42 accumulates in engulfing cells at membranes surrounding apoptotic corpses. The formation of such halos depends on the integrins PAT-2/PAT-3, UNC-112 and the GEF protein UIG-1, but not on the canonical ced-1/6/7 or ced-2/5/12 signaling modules. Together, our results suggest that the small GTPase CDC-42 regulates apoptotic cell engulfment possibly upstream of the canonical Rac GTPase CED-10, by polarizing the engulfing cell toward the apoptotic corpse in response to integrin signaling and ced-1/6/7 signaling in C. elegans.
Insights
The small GTPase CDC-42 is newly identified to regulate cell corpse clearance in C. elegans. It acts upstream of CED-10/Rac1, potentially polarizing engulfing cells via integrin and CED-1/6/7 signaling.
Area of Science:
- Cell Biology
- Developmental Biology
- Genetics
Background:
- Efficient removal of apoptotic cells is crucial for multicellular organism health.
- In C. elegans, cell corpse engulfment involves parallel signaling pathways, including GTPases MIG-2/RhoG and CED-10/Rac1.
Purpose of the Study:
- To identify and characterize novel GTPases involved in cell corpse clearance.
- To elucidate the regulatory role and signaling interactions of CDC-42 in apoptotic cell engulfment.
Main Methods:
- Genetic analysis using cdc-42 loss-of-function and overexpression mutants in C. elegans.
- Localization studies of CDC-42 in engulfing cells.
- Investigating the dependence of CDC-42 accumulation on other signaling components.
Main Results:
- CDC-42 was identified as a third GTPase regulating cell corpse clearance.
- cdc-42 functions in parallel to or upstream of the CED-10/Rac1 module and downstream of the CED-1/6/7 module.
- CDC-42 accumulation at the engulfing cell membrane requires integrins (PAT-2/PAT-3, UNC-112) and UIG-1, but not canonical engulfment modules.
Conclusions:
- CDC-42 plays a significant role in apoptotic cell engulfment, likely by polarizing the engulfing cell.
- CDC-42 acts upstream of CED-10/Rac1, integrating signals from integrins and the CED-1/6/7 pathway.
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