Gulping rather than sipping: macropinocytosis as a way of virus entry

Mercer, Jason; Helenius, Ari

doi:10.1016/j.mib.2012.05.016

Cited by 186 publications

(259 citation statements)

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“…31 Virus particles first activate signaling pathways that trigger actin-mediated membrane ruffling and blebbing. In the next stage, the 'collapse' of these cytoskeletal structures induces the formation of large vacuoles (macropinosomes) at the plasma membrane, resulting in internalization of virus particles and subsequent penetration into the cytosol.…”

Section: Macropinocytosismentioning

confidence: 99%

“…PAK activation contributes to the initial stages of actin remodeling and is later also involved in the macropinosome closure by activating C-terminal-binding protein-1/brefeldin A-ADP ribosylated substrate (CtBP-1 also known as BARS). 31,32,37,[76][77][78][79] Macropinocytic uptake has been reported for many viruses including, among others, poxviruses, Ebola virus, influenza virus, adenoviruses, herpesviruses and retroviruses. For example, several labs have reported on the role of Rho GTPases and macropinocytosis during vaccinia virus (VV) entry 27,37,77,78,80 For an extensive overview of the (subtle) differences in macropinocytic uptake between the different viruses we refer to a review by Mercer and Helenius.…”

Section: Macropinocytosismentioning

confidence: 99%

“…For example, several labs have reported on the role of Rho GTPases and macropinocytosis during vaccinia virus (VV) entry 27,37,77,78,80 For an extensive overview of the (subtle) differences in macropinocytic uptake between the different viruses we refer to a review by Mercer and Helenius. 31 More recently, actin-dependent macropinocytosis-like uptake has been described for human papillomavirus type 16. 81 Also recently, macropinocytic uptake has been suggested for two herpesviruses, the betaherpesvirus HCMV and the gammaherpesvirus KSHV.…”

Section: Macropinocytosismentioning

confidence: 99%

“…Indeed, Rho GTPase signaling is involved in the intrinsic signaling pathways that drive different endocytic uptake processes that may be (mis) used by viruses, particularly phagocytosis and macropinocytosis. [22][23][24][25][26][27][28][29][30][31][32][33][34] On the other hand, fusogenic uptake may not directly depend on Rho signaling, but, upon fusion, local actin rearrangements might be required to allow passage of the capsids through the cortical actin meshwork underneath the plasma membrane. Viral surfing and receptor clustering Several viruses, including retroviruses, papillomaviruses, herpesviruses, poxviruses, dengue virus and vesicular stomatitis virus (VSV), engage Rho GTPase signaling even before entering the cell.…”

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Rho’ing in and out of cells

2014

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These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

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Section: Macropinocytosismentioning

confidence: 99%

Section: Macropinocytosismentioning

confidence: 99%

Section: Macropinocytosismentioning

confidence: 99%

mentioning

confidence: 99%

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Rho’ing in and out of cells

2014

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“…To date, over 20 different viruses from diverse families have been shown to use macropinocytosis for infectious entry (reviewed in 15 31). Amongst these is vaccinia virus (VACV), a large, enveloped, dsDNA virus characterized by its structural complexity and cytoplasmic life cycle.…”

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Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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The prototypic poxvirus, vaccinia virus (VACV), occurs in two infectious forms, mature virions (MVs) and extracellular virions (EVs). Both enter HeLa cells by inducing macropinocytic uptake. Using confocal microscopy, live‐cell imaging, targeted RNAi screening and perturbants of endosome maturation, we analyzed the properties and maturation pathway of the macropinocytic vacuoles containing VACV MVs in HeLa cells. The vacuoles first acquired markers of early endosomes [Rab5, early endosome antigen 1 and phosphatidylinositol(3)P]. Prior to release of virus cores into the cytoplasm, they contained markers of late endosomes and lysosomes (Rab7a, lysosome‐associated membrane protein 1 and sorting nexin 3). RNAi screening of endocytic cell factors emphasized the importance of late compartments for VACV infection. Follow‐up perturbation analysis showed that infection required Rab7a and PIKfyve, confirming that VACV is a late‐penetrating virus dependent on macropinosome maturation. VACV EV infection was inhibited by depletion of many of the same factors, indicating that both infectious particle forms share the need for late vacuolar conditions for penetration.

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Attacking the supply wagons to starve cancer cells to death

et al. 2016

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The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death.

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Gulping rather than sipping: macropinocytosis as a way of virus entry

Cited by 186 publications

References 89 publications

Rho’ing in and out of cells

Rho’ing in and out of cells

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Attacking the supply wagons to starve cancer cells to death

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