Rab GTPases act in sequential steps to regulate phagolysosome formation

Abstract

During apoptosis, apoptotic cells are recognized and quickly engulfed by phagocytes. The internalized cell corpses are enclosed within membrane-bound vesicles called phagosomes. Cell corpse degradation depends on the phagosomes undergoing a maturation process, but regulation of phagosomal maturation is not well understood. Recently, we identified C. elegans Rab GTPase 14 as a novel regulator of apoptotic cell degradation. Loss of rab-14 function affects several steps of phagosome maturation, causing accumulation of persistent cell corpses. RAB-14 and UNC-108 (Rab GTPase 2) function redundantly to regulate phagosome maturation. Three Rabs, RAB-14, UNC-108/RAB2, and RAB-7, act cooperatively to control phagolysosome formation. RAB-14 and UNC-108 recruit lysosomes, while RAB-7 mediates fusion of lysosomes to phagosomes. Our data thus reveal the sequential action of Rab GTPases in regulating tethering, docking and fusion of lysosomes to phagosomes.

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Acknowledgements

This work was supported by the National High Technology Project 863 to X.W.

Figures and Tables

Figure 1 Multiple Rabs cooperate to regulate phagosome acidification and phagolysosome formation for apoptotic cell degradation in C. elegans. (A) RAB-14 and UNC-108/RAB2 may act sequentially to deliver V-type ATPase to apoptotic cell-containing phagosomes. UNC-108 mainly associates with vesicles derived from the trans-Golgi network (TGN) and promotes the transport of V-type ATPase to early endosomes. RAB-14 functions in the following step to deliver V-type ATPase to phagosomes by mediating the tethering, docking and fusion of early endosomes to phagosomes through the recruitment of tethering effectors. The acquisition of V-type ATPase initiates phagosomal acidification. (B) RAB-14, UNC-108 and RAB-7 act in sequential steps to regulate phagolysosome formation. RAB-14 and UNC-108 recruit lysosome-targeting tethers as effectors to bring lysosomes in close contact with phagosomes. RAB-7 acts in the next step to mediate lysosome docking and fusion by promoting SNARE paring and complex formation. The HOPS complex may serve as the effector for both UNC-108 (RAB-14) and RAB-7 to coordinate the tethering and fusion of lysosomes to phagosomes.

Extra View to: Guo P, Hu T, Zhang J, Jiang S, Wang X. Sequential action of Caenorhabditis elegans Rab GTPases regulates phagolysosome formation during apoptotic cell degradation. Proc Natl Acad Sci USA 2010; 107:18016 - 18021; PMID: 20921409; http://dx.doi.org/10.1073/pnas.1008946107

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