Abstract
Much remains unknown about mechanisms sustaining the various stages in the life cycle of neurotropic viruses. An understanding of those mechanisms operating before their replication and propagation could advance the development of effective anti-viral strategies. Here, we review our current knowledge of strategies used by neurotropic viruses to undergo bidirectional movement along axons. We discuss how the invasion strategies used by specific viruses might influence their mode of interaction with selected components of the host’s fast axonal transport (FAT) machinery, including specialized membrane-bounded organelles and microtubule-based motor proteins. As part of this discussion, we provide a critical evaluation of various reported interactions among viral and motor proteins and highlight limitations of some in vitro approaches that led to their identification. Based on a large body of evidence documenting activation of host kinases by neurotropic viruses, and on recent work revealing regulation of FAT through phosphorylation-based mechanisms, we posit a potential role of host kinases on the engagement of viruses in retrograde FAT. Finally, we briefly describe recent evidence linking aberrant activation of kinase pathways to deficits in FAT and neuronal degeneration in the context of human neurodegenerative diseases. Based on these findings, we speculate that neurotoxicity elicited by viral infection may involve deregulation of host kinases involved in the regulation of FAT and other cellular processes sustaining neuronal function and survival.
Highlights
The large size and highly polarized cellular architecture of neurons present a major challenge for the replication and propagation of neurotropic viruses
Using lysates prepared from HEp-2 cells infected with herpes simplex virus type 1 (HSV-1) as starting material, the tegument protein pUS11 was found to co-precipitate with bacterially expressed, recombinant KIF5B in pull-down assays (Diefenbach et al, 2002), but whether this protein behaves as conventional kinesin holoenzyme is unclear
The membrane-associated tegument protein pUL56 of HSV-2 was proposed to be an anterograde fast axonal transport (FAT) effector based on data from yeast two-hybrid system and pull-down assays showing an interaction with the kinesin-related motor protein KIF1A (Koshizuka et al, 2005)
Summary
The large size and highly polarized cellular architecture of neurons present a major challenge for the replication and propagation of neurotropic viruses. A mechanistic basis for the effect of some protein kinases on FAT remains unknown, but several have been shown to impact specific functional activities of CDyn and conventional kinesin (i.e., binding to MBO cargoes or microtubules) through direct phosphorylation of specific subunits (reviewed in Gibbs et al, 2015; Morfini et al, 2009a).
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