Upon entry into cells, many diverse viruses exploit their hosts' cytoskeletal transport networks to reach their sub-cellular site of replication, and nw viral progeny use these same networks to return to the cell surface and spread. Viruses frequently move along actin at the cell periphery before transitioning onto host microtubule (MT) networks that mediate long-range intracellular transport. MTs are highly dynamic heteropolymers of / tubulin (half-lives <5 min), which radiate from the perinuclear MT Organization Center (MTOC) towards the cell surface. Subsets of MTs become stabilized (half-life >1h) in response to various environmental and developmental signals, and are thought to act as specialized networks for vesicle transport during events such as cell polarization and motility. MT dynamics and stabilization are controlled by a number of highly specialized regulators, including actin-MT crosslinking factors and MT plus-end binding proteins (+TIPs), whose accumulation at MT ends is facilitated by the MT plus-end tracking protein, EB1. Movement of cargos on these MT networks involves motor proteins; generally, dynein directs minus-end and kinesins direct plus-end transport. However, our understanding of the role of MTs, their regulators and motors in the movement of viral particles during infection is severely limited. This Program Project Grant (PPG) nucleates expertise in cytoskeletal regulation, motors and MT-based motility, cell signaling and infection by diverse viruses to address these fundamental questions in mechanistic detail in a variety of systems. As a group, our interactions to date have established that both RNA and DNA viruses cause distinct MT modifications and require a range of specialized MT regulatory factors for efficient infection, including actin-MT crosslinkers, +TIPs and EB1, as well as identifying specific host motors used for virion traffickin to the nucleus. In this PPG we aim to determine the mechanistic details underlying these highly dynamic interactions between MT subsets, motors and invading virions, including the use of state-of-the-art dual-color imaging to analyze these events in real time. This integrated and interactive approach not only greatly enhances each individual project's potential by leveraging the strengths of other members, but also serves to focus our cumulative expertise on addressing key aspects of the Overall Aims of this PPG, Microtubule Networks and Virus Trafficking. This efficient group approach has the potential to uncover fundamental new insights in MT function and regulation during viral infection that will likely be important in broaer biological contexts and may lead to the development of novel therapeutic approaches.
The dynamics and stability of microtubule networks are carefully controlled by an array of specialized regulatory factors, mediating changes in cell structure and motor-driven movement of cargos throughout the cell. However, our understanding of the role of these networks, motors and regulators in the movement of viruses is severely limited. This Program Project Grant aims to determine the molecular details by which these factors function in infection by distinct RNA and DNA viruses, filling a large gap in our understanding of how these pathogens replicate that could be exploited to develop novel antiviral strategies and will also add to our broader knowledge of fundamental mechanisms of MT regulation and MT-based movement.
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|Bartolini, Francesca; Andres-Delgado, Laura; Qu, Xiaoyi et al. (2016) An mDia1-INF2 formin activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells. Mol Biol Cell 27:1797-808|
|Jovasevic, Vladimir; Naghavi, Mojgan H; Walsh, Derek (2015) Microtubule plus end-associated CLIP-170 initiates HSV-1 retrograde transport in primary human cells. J Cell Biol 211:323-37|
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