Abstract
F-Actin remodeling is important for the spread of HIV via cell–cell contacts; however, the mechanisms by which HIV corrupts the actin cytoskeleton are poorly understood. Through live cell imaging and focused ion beam scanning electron microscopy (FIB-SEM), we observed F-Actin structures that exhibit strong positive curvature to be enriched for HIV buds. Virion proteomics, gene silencing, and viral mutagenesis supported a Cdc42-IQGAP1-Arp2/3 pathway as the primary intersection of HIV budding, membrane curvature and F-Actin regulation. Whilst HIV egress activated the Cdc42-Arp2/3 filopodial pathway, this came at the expense of cell-free viral release. Importantly, release could be rescued by cell–cell contact, provided Cdc42 and IQGAP1 were present. From these observations, we conclude that a proportion out-going HIV has corrupted a central F-Actin node that enables initial coupling of HIV buds to cortical F-Actin to place HIV at the leading cell edge. Whilst this initially prevents particle release, the maturation of cell–cell contacts signals back to this F-Actin node to enable viral release & subsequent infection of the contacting cell.
Highlights
Actin is a major component of the cellular cytoskeleton and is present in both monomeric globular (G-actin) and polymeric filamentous (F-actin) forms in all eukaryotic cells
Given the proposed role of Arp2/3 and formins in filopodia formation in other cell types, we initially focused on these key actin regulators for depletion
Disruption of filopodial networks was assessed by measuring filopodial abundance and length
Summary
Actin is a major component of the cellular cytoskeleton and is present in both monomeric globular (G-actin) and polymeric filamentous (F-actin) forms in all eukaryotic cells. The two major classes of cellular actin nucleators are the Arp2/3 complex and formins. The Arp2/3 complex is composed of seven different subunits and allows formation of branched actin networks through nucleation of a branch filament from an existing mother filament at an angle of 70 degrees [1]. Formins are large multidomain proteins that drive nucleation and/or elongation of unbranched linear actin filaments. The activity of cellular Arp2/3 and formins is tightly regulated by a complex network of signalling pathways that primarily rely on the molecular switch properties of Rho-GTPases, such as Rac and Cdc, for their activation [2]
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