The possible roles of Rab11-positive recycling endosomes in cytokinesis of mammalian somatic cell
Background
Cytokinesis is an independent event from mitosis
Cytokinesis is the final step of cell division, and by which the cytoplasm is divided into two daughter cells. Traditionally and on most textbooks, cytokinesis has been grouped together with mitosis and thought as the last step in mitosis. For some organisms such as Schizosaccharomyces pombe 1 and Saccharomyces cerevisiae 2, however, cytokinesis can be uncoupled from mitosis. Moreover, early Drosophila embryo forms the syncitium by having thirteen rounds of mitosis without cytokinesis 3, suggesting mitosis is also not always followed by cytokinesis. Therefore mitosis and cytokinesis could be considered as two individual events in cell cycle. Mammalian cytokinesis usually starts in late anaphase when myosin/actin-based contractile ring begins to construct around the cell 4. The molecular motor, Myosin II, slides actin filaments across each other, driving the ring contraction and the plasma membrane furrowing from equatorial cortex. This contractile ring pinches the cell in a purse-string fashion and the furrow proceeds ingression until it reaches midzone microtubules 5. At this time the furrowed junction between daughter cells is shaped as a bridge-like structure, called midbody. Later the actomyosin ring disassemblies and midbody gradually decreases its diameter and finally abscises into two individual cells.
Vesicle trafficking in cleavage furrow is well conserved in eukaryotic cytokinesis
During furrow ingression, surface area increases rapidly and it needs new membrane added on the surface to fulfill the demand. Most eukaryotic cells appear to have a vesicle transport system toward the cleavage furrow to compensate the requirement 6 and membrane addition at the cleavage furrow appears to be necessary for cytokinesis completion 7,8. In recent years, due to the advances in microscopy, membrane/vesicles trafficking to cleavage furrow surface has been widely observed in different organisms such as Drosophila embryos 9,10, Xenopus laevis eggs 11-13, and Danio rerio (zebrafish) blsatomeres 14, demonstrating it is a fundamental and widely conserved mechanism in animal cytokinesis. However, compared to our understanding about the contractile ring, vesicle trafficking steps during cytokinesis have been far less characterized. It appears vesicles are targeting to specific areas in cleavage furrow. In Xenopus embryo, delivered vesicles appear to be restricted to the cleavage plane and vesicle fusion occurs near the leading edge of the furrow 13,15. Similarly, study in Drosophila also demonstrated that many small vesicles aligned in front of the invaginating furrow 16. It suggests the vesicle trafficking in cytokinesis is a tightly regulated event and carried out in a temporally and spatially regulated manner. However, most of our knowledge is coming from embryo studies. Although vesicles delivered to cleavage furrow can also be observed in somatic cells, it is not clear if there is any new membrane added to cleavage furrow as embryo cells do. Unlike embryos, in cultured mammalian cells, the new membranes are generated throughout the whole cell cycle, not only in mitosis or cytokinesis. When somatic cells enter mitosis and round up, excess membranes could be stored as microprojections on the surface and might be sufficient for furrow ingression. Thus the demand for adding new membrane to cleavage furrow is not that urgent in somatic cells. It has been known that the membrane composition of protein and lipid in cleavage furrow is distinct to the rest parts of plasma membrane 8,17-20. Thus, in addition to membranes, vesicle trafficking could also mediate the delivery of proteins which regulate the furrow ingression and midbody abscission in cytokinesis. Together, vesicle trafficking may be necessary for recruiting specific proteins or lipids which are required for cytokinesis progression. It reflects a requirement to couple membrane insertion and protein recruitment to coordinate the cortex remodeling activity and intracellular guiding signal in cytokinesis.
Recycling endosomes might be the source of vesicles in cleavage furrow
There are two possible sources for membrane trafficking/addition in cytokinesis, post-Golgi secretory, and recycling pathway vesicles. Both pathways are proved essential in cytokinesis 21. By treating Caenorhabditis elegans embryos with brefeldin A (BFA), an Arf GTPase inhibitor that blocks anterograde transport from ER and ultimately results in Golgi disassembly, the cleavage furrow appears normal in the initial and progression steps. However, BFA blocks the final abscission which might need new membrane to seal the midbody in a plant phragmoplast (cell plate)-like fashion 13,22. Similar conclusions have also been drawn in human epithelial cells that BFA inhibits the terminal abscission step but has no effect on furrowing process 22-24. Post-Golgi secretory can only happen after the midbody is fully formed and vesicles are directly delivered from cell body to cytoplasmic bridge, without any accumulation near the cleavage furrow 24. Therefore, it is more likely that Golgi-derived vesicles are specifically required at the abscission stage but not in earlier furrowing stages. On the other hand, recent studies indicate blocking endocytic activities also leads to cytokinesis defects in Dictyostelium discoideum 25, Drosophila 26,27, C. elegans 28, and zebrafish embryos 14. Among different endocytic compartments, some features make recycling endosomes (REs) a well-suited candidate for the membrane or vesicles source at cleavage furrow. Although it has been reported that REs can transport vesicles to Golgi or other endosomal compartment, the primary destination for RE-derived vesicle is the plasma membrane. In addition to membrane delivery, REs also play a role sorting different proteins to specific regions of plasma membrane. Besides, REs associated with microtubules and centrosomes can be highly regulated and coupled with cleavage furrow positioning. While endocytosis ceases during the early stages of mitosis, it resumes coupling the start of cytokinesis in late anaphase 29. Blocking this endocytosis inhibits the completion of cytokinesis, suggesting a proper regulation of REs mediated endosomal membrane trafficking is necessary for cytokinesis 29.
Rab11 and effector protein FIP3 localize at REs and are both essential for cytokinesis
The first functional evidence implicating REs to cytokinesis came from the RNAi-induced Rab11 depletion in C. elegans embryos, in which Rab11 siRNA blocks cytokinesis at both furrowing and abscission stages 22. Rab11-containing vesicles were also required for Drosophila furrow formation during cellularization and it was proposed Rab11 GTPase may regulate RE vesicles to the cleavage furrow 30,31. Rab11 is a member of Rab proteins which constitute the largest family of small monomeric GTPases and play an important role in various membrane trafficking pathways. Rab11 localizes predominantly on RE compartment and has been shown to be essential for proper RE organization and recycling vesicles from RE to the plasma membrane 32,33. Like other GTPases, the cycling between GTP and GDP bound forms regulates Rab proteins recruiting various effector proteins toward cellular membranes, and recruited effector proteins further regulate the targeting and fusion of transport vesicles 34. Recently, several Rab11 effector proteins have been identified 35-39. Four proteins contain the highly conserved motif known as Rab11-Binding-Domain (RBD) have been grouped together as family of Rab11-interacting proteins (FIPs), FIP1 to FIP4 36,40. Two of them, FIP3 and FIP4, share a degree of homology with Drosophila Nuclear Fallout protein which is required for cellularization. And indeed, FIP3 and FIP4 have been shown to play a role in mammalian cytokinesis 41. In addition, FIP3 has also been identified as an interacting protein of ARF6, a GTPase located on cleavage furrow when activated 38,42.
Rab11-REs play an essential role in abscission step of cytokinesis
The intracellular localization of Rab11-containing REs (Rab11-REs) during cytokinesis appears to be a tightly regulated event. After cytokinesis onset, RE compartments are reorganized by activated Rab11 and FIP3 is also recruited to Rab11-REs. Reorganized Rab11-REs concentrate around centrosomes 41. At the later stage of cleavage furrow ingression, Rab11-REs rapidly translocate from centrosomes to cleavage furrow by an unknown mechanism. After midbody completely forms, Rab11-REs are localized in midbody [Figure 1]. Arf6 has been reported to recruit Rab11-REs to furrow and midbody region through interacting Rab11 effector protein FIP3 in Rab11-REs 42. Indeed, RNAi depletion of any of Rab11, FIP3 and ARF6 results in similar phenotype with significantly increased number of bi-nuclei cells 41,42. Depleted cells are missing the abscission step and remain connected by a long cytoplasmic bridge for a very long time and finally proceed apoptosis or furrow regression. It suggests Rab11, FIP3 and ARF6 may function in the same signal pathway regulating abscission and are all essential for cytokinesis completion 41.
For the signal pathway for regulating abscission in cytokinesis, Centriolin arrives at midbody after cleavage furrowing complete, and later SNAP and Exocyst are recruited to Centriolin in midbody. After the contractile ring disassemblies, the midbody diameter decreases, and then SNAREs join Centriolin/Exocyst/Snapin complex and recruiting the post-Golgi vesicles to seal the midbody triggering abscission 24. Again, although the scaffold of the signal pathway is known, all fine-tune parts are missing, for example, how those proteins are recruited to midbody and what triggers it, or how this signal pathway couple and communicate to furrow ingression. Besides, because depletion of Rab11 blocks the abscission, it indicates Rab11-REs may also participate in this pathway, but at which step and how are also obscure.
Significance of vesicle trafficking study in cell division
Cell division is required for the propagation of all livings and cytokinesis is the last stage in it. Cytokinesis, therefore could be a potential therapeutic target for drugs, and its inhibition might prevent excessive cell proliferation as occurs in cancer 43. Vesicle trafficking in cytokinesis is a relatively unknown field in cell division studies. In this proposal, important questions such as the triggering mechanism for vesicle trafficking, target sites of membrane insertion, and possible roles in abscission will all be addressed. Knowing answers for those questions should benefit the studies in cell division and also the application such as cancer therapy.
2 comments:
Hi, I am very interested in your PQE proposal, so just wondered if you can post me all references you have used in the proposal?
my email hugo.zheng@mcgill.ca
Here you go! Enjoy!
Here is a link for the list:
http://www.yousendit.com/download/WnBRblR1K3g5bENGa1E9PQ
Reference
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