Actin and Rho GTPases in herpesvirus biology

Abstract

Viruses have evolved a variety of interactions with host cells to create an optimal niche for viral replication, persistence and spread. The actin cytoskeleton of the host cell and actin-regulating Rho GTPase signaling pathways can be involved in several of these interactions. This review focuses on recent findings on herpesvirus interactions with actin and Rho GTPases during viral entry, replication in the nucleus and egress. Unraveling these often fascinating interactions might also provide additional insights into sometimes poorly known aspects of actin biology (e.g. its role in the nucleus) and in the development of novel antiviral therapies.Actin filaments and actin-regulating Rho GTPase signaling pathways Filamentous actin is a key structure of the cytoskeleton in every cell. The actin cytoskeleton is involved in many crucial cellular processes, including providing cell integrity, mobility and shape; driving cell division and contraction; and the uptake of extracellular molecules.Actin filaments consist of polarized ATP-bound globular actin monomers. These filamentous actin (F-actin) molecules can associate into bundles or networks through actin cross-linking molecules. The best characterized F-actin bundles and networks are filopodia, lamellipodia and actin stress fibers. Formation of the different actin bundles and networks is regulated by signal transduction pathways that depend on small Rho GTPases [1]. Of the 22 identified mammalian Rho GTPases, the best characterized are RhoA (stress fibers), Rac1 (lamellipodia) and Cdc42 (filopodia). These Rho GTPases act as molecular switches and alternate between their active GTP-bound form and their inactive GDP-bound form. Transition from the active to the inactive form is accompanied by phosphorylation and activation of different downstream effector molecules that initiate signal transduction pathways and subsequent rearrangements in the actin cytoskeleton. These three signal transduction pathways are interwoven and the RhoA pathway generally counteracts the Rac1 and Cdc42 pathways [2]. Details of Rho GTPase signaling networks can be found elsewhere [3].Because of the many cellular functions in which they are involved, it comes as no surprise that many intracellular pathogens interact with actin and actin-regulating signaling pathways. These interactions can occur at several points in the life cycle of the pathogens, including, although not limited to, internalization, intracellular movement and intercellular spread [4,5].There are recent indications that, in particular cell types, herpesviruses also interact with actin and/or Rho GTPases during three major phases of the replication cycle of herpesviruses: entry into the cytoplasm, replication and assembly in the nucleus and maturation and egress. This review presents an overview of these data and points to future directions in research in this new and potentially important field of herpesvirus biology. Special attention is given on the alphaherpesvirus subfamily of herpesviruses, but relevant references to wor...

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

“…These projections extend to neighboring cells (Fig. 3C) and similar cell projections at late stages of infection have been detected in several a-herpesviruses, such as HSV-1, VZV and PRV enhancing the intercellular viral spread (for review 35,36,39,40 ).…”

“…There is increasing evidence that herpesviruses are capable of usurping Rho GTPases during the main stages of the viral lifecycle, such as virus entry, translocation of the viral particles to the nucleus and viral egress. 35,36 Depending on the endocytic uptake routes engaged during the initial interaction of the herpesviruses with the host, specific Rho GTPase signaling is triggered and significant actin cytoskeleton rearrangements are induced, [37][38][39][40] creating an optimal microenvironment for viral replication, persistence and dissemination. It is of interest that apart from lytic infection, the interactions between gamma-herpeviruses and Rho GTPase signaling remain active even during non-productive infection, facilitating either the establishment of latency 41 or affecting cell motility and invasion and promoting the oncogenic properties of these viruses.…”

Cross-talk between Rac1 and Cdc42 GTPases regulates formation of filopodia required for dengue virus type-2 entry into HMEC-1 cells

“…It has been reported that herpes simplex and Epstein-Barr viruses activate Rac1 and Cdc42 GTPases to form lamellipodia and filopodia in epithelial cells and fibroblasts (Melamed et al, 1994;Favoreel et al, 2007). Thus, signalling pathways, known to regulate the formation of filopodia, were analysed after DENV-2 binding to HMEC-1 cells.…”

“…In cells pretreated with blebbistatin, some filopodia were induced by DENV-2, although the filopodia that were formed were unstable. It has been reported that filopodial activity and surfing of murine leukemia virus in host cells depend on actin dynamics and motor activity of myosin II and other non-conventional myosins such as myosin V and myosin X (Lehmann et al, 2005;Favoreel et al, 2007;Ikebe, 2008;Mattila & Lappalainen, 2008). Unfortunately, myosins in HMEC-1 cells have not been characterized.…”

Replication kinetics of neuropathogenic and non-neuropathogenic equine herpesvirus type 1 (EHV-1) strains in primary murine neurons and ED cell line

“…It seems that the neuropathogenic EHV-1 strain uses the same strategy to infect adjacent cells as the Jan-E EHV-1 (Słońska et al 2014). The literature data suggest that other herpesviruses also induce the formation of similar actin projections -HHV-1 in the Vero cells and BHK, VZV in the HFF cells or SuHV-1 in RK13 and PK15 cells (Favoreel et al 2005(Favoreel et al , 2007.…”