Reconsidering an active role for G-actin in cytoskeletal regulation

Abstract

Globular (G)-actin, the actin monomer, assembles into polarized filaments that form networks that can provide structural support, generate force and organize the cell. Many of these structures are highly dynamic and to maintain them, the cell relies on a large reserve of monomers. Classically, the G-actin pool has been thought of as homogenous. However, recent work has shown that actin monomers can exist in distinct groups that can be targeted to specific networks, where they drive and modify filament assembly in ways that can have profound effects on cellular behavior. This Review focuses on the potential factors that could create functionally distinct pools of actin monomers in the cell, including differences between the actin isoforms and the regulation of G-actin by monomer binding proteins, such as profilin and thymosin β4. Owing to difficulties in studying and visualizing G-actin, our knowledge over the precise role that specific actin monomer pools play in regulating cellular actin dynamics remains incomplete. Here, we discuss some of these unanswered questions and also provide a summary of the methodologies currently available for the imaging of G-actin.

Profilin and formin constitute a pacemaker system for robust actin filament growth

“…Such a monomer-triggered mechanism has been proposed for formin-mediated nucleation after cell deformation (Higashida et al, 2013). Ways to detect distinct soluble actin states in vivo are needed to understand their effect on local actin network dynamics (Skruber et al, 2018). (F) Barbed end growth velocities of filaments grown in microfluidic channels in TIRFM assays (green) compared to surface tethered filaments as quantified in ((C), black dashed line).…”

“…Actin assembly requires nucleation of filaments, which elongate by the addition of subunits to filament ends. To move and quickly adapt their shape, most eukaryotic cells sustain vast amounts (>50uM) of polymerizable subunits, which requires the monomer-binding protein profilin (Koestler et al, 2009;Pollard et al, 2000;Raz-Ben Aroush et al, 2017;Skruber et al, 2018). Profilin shields the barbed end side of actin monomers to suppress spontaneous nucleation .…”

“…ii) Generally, soluble actin concentrations vary significantly across species, cell types (Koestler et al, 2009;Pollard et al, 2000;Raz-Ben Aroush et al, 2017) and likely even within a single cell (Skruber et al, 2018). If elongation rates scale linearly with profilin-actin concentrations, then actin filaments must grow at widely different speeds in vivo.…”

Genetic interaction between profilin and myosin II reveals a potential role for myosin II in actin filament disassemblyin vivo

“…Actin is a highly conserved cytoskeletal polymer forming protein that is key to a vast array of physiological processes in the three domains of life. In eukaryotes, the actin cytoskeleton plays essential roles in cell polarity, morphogenesis, migration, and cytokinesis (Pollard and Wu 2010, Cheffings, Burroughs et al 2016, Misu, Takebayashi et al 2017, Rottner, Faix et al 2017, Skruber, Read et al 2018. A balance of factors that control filament nucleation and stability and those that promote its disassembly exquisitely regulates the functions of the actin cytoskeleton (Lee and Dominguez 2010).…”

Profilin 1 Controls the Assembly, Organization, and Dynamics of Leading Edge Actin Structures Through Internetwork Competition and Collaboration

“…To meet the demands of actin network assembly, cells maintain a large monomer reserve (1-4). However, several factors complicate how monomers are distributed to different actin structures within the cell (5). For example, monomers can undergo biased assembly into specific networks through interactions with polymerases and monomer-binding proteins (6,7).…”