Abstract
The cellular actin cytoskeleton presents a barrier that must be overcome by many viruses, and it has become increasingly apparent many viral species have developed a diverse repertoire of mechanisms to hijack cellular actin-regulating signalling pathways as part of their cell entry processes. The Rho family GTPase Cdc42 is appreciated as a key moderator of cellular actin dynamics, and the development of specific Cdc42-inhibiting agents has given us an unprecedented ability to investigate its individual role in signalling pathways. However, investigative use of said agents, and the subsequent characterisation of the role Cdc42 plays in viral entry processes has been lacking. Here, we describe the current literature on the role of Cdc42 in human immunodeficiency virus (HIV)-1 cell entry, which represents the most investigated instance of Cdc42 function in viral cell entry processes, and also review evidence of Cdc42 use in other RNA virus cell entries, demonstrating prime areas for more extensive research using similar techniques.
Highlights
The cellular actin cytoskeleton is not a static phenomenon solely providing structural integrity to cells, and is instead constitutionally active throughout cellular life and involved in key processes such as intracellular organisation, motility, and intracellular transport within and out of cells [1,2,3]
In human immunodeficiency virus (HIV)-1 this involvement of Cdc42 has been most thoroughly characterised, likely because of its global burden and the ongoing exploration of the viral lifecycle warranted in the hope of identifying new potential drug targets
Whilst a spectrum of techniques ranging from the broader use of general actin inhibition, to more targeted investigations with small interfering RNAs (siRNAs) knockdowns of specific signalling-related genes, have provided the bulk of initial data for HIV-1 Cdc42 use, it has only been through employing novel Cdc42-specific agents that the clearest indications of Cdc42 use have been elucidated
Summary
The cellular actin cytoskeleton is not a static phenomenon solely providing structural integrity to cells, and is instead constitutionally active throughout cellular life and involved in key processes such as intracellular organisation, motility, and intracellular transport within and out of cells [1,2,3]. The Rho family GTPases constitute a diverse group of cell signalling molecules present in all eukaryotic organisms, and play an integral role in the control of cellular actin dynamics, cumulating in macro-effects on cell morphology, membrane trafficking, and adhesions. MMoosstt RRhhoo GGTTPPaasseess bbiinndd ttoo bbootthh GGTTPP aanndd GGDDPP,, aarree ccaappaabbllee ooff eexxeerrttiinngg iinnttrriinnssiicc GGTTPPaassee aaccttiivviittyy. CCyycclliinngg bbeettwweeeenn tthhee aaccttiivvee GGTTPP--bboouunndd aanndd iinnaaccttiivvee GGDDPP--bboouunndd ssttaattee ccaann ssppoonnttaanneeoouussllyy ooccccuurr iinn RRhhoo GGTTPPaasseess dduuee ttoo tthheeiirr iinnttrriinnssiicc GGTTPPaassee aaccttiivviittyy,,bbuuttwwiitthhiinncceellllss iiss rreegguullaatteeddbbyy tthhrreeeeccllaasssseess ooff rreellaatteedd mmoolleeccuulleess:: gguuaanniinnee eexxcchhaannggee ffaaccttoorrss ((GGEEFFss)),, GGTTPPaassee aaccttiivvaattiinngg pprrootteeiinnss ((GGAAPPss)),, aanndd gguuaanniinnee nnuucclleeoottiiddee--ddiissssoocciiaattiioonniinnhhiibbiittoorrss((GGDDIIss)). TThhiiss ccaann bbee ddeemmoonnssttrraatteedd bbyy ccoonnssiiddeerriinngg tthhee LLIIMM ddoommaaiinn kkiinnaassee ((LLIIMMKK))ss--ccoofifilliinn ppaatthhwwaayy,, wwhhiicchh nnoott oonnllyy uunniitteess aallll tthhrreeee mmaajojorr RRhhoo GGTTPPaasseess,, bbuutt iiss aallssoo ccaappaabbllee ooff bbootthh FF--aaccttiinn ppoollyymmeerriissaattiioonn aanndd ddee--ppoolylymmeerrisisaatitoionn eefffefecctsts. IPA-3 is a small molecule inhibitor of downstream Cdc signalling, selectively inhibiting group 1 PAKs by targeting the auto-regulatory mechanism present in this group
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