Editorial: Evolution, Emerging Functions and Structure of Actin-Binding Proteins

Actin is an essential cytoskeletal protein that provides structural support for multiple cellular processes including cellular motility, division and contractility (Pollard and Goldman, 2018). Actin filaments exist in association with binding partners, mainly actin-binding proteins (ABPs) that together control the many functions of the actin cytoskeleton (Lehman and Maeda, 2020). ABPs can bind actin monomers, polymers or both and more than 160 ABPs have been identified to date (Winder and Ayscough, 2005). However, classification of ABPs is difficult because actin binding is a common process, but can result in a plethora of different functional outcomes. Therefore, attempts to classify ABPs has left many “orphans” that do not fit into families (dos Remedios et al., 2003). Generally, ABPs can be divided into two broad categories, depending on their effect on actin filament dynamics (Stehn et al., 2006). The first category of ABPs regulates the G-actin/F-actin turnover thus controlling cytoskeletal responses to external stimuli. This category includes Arp2/3, ADF/cofilin, profilin, gelsolin, etc (Stehn et al., 2006). The second general category of ABPs helps actin filamnets to form higher order structures, such as actin filaments meshworks or bundles. This category includes tropomyosin, caldesmon, filamin, dystrophin, among others (Stehn et al., 2006). ABPs also link actin filaments to the plasmamembrane, thus facilitating outside-in and inside-out signaling (Figure 1). For example, dystrophin anchors the actin cytoskeleton to membrane glycoproteins such as β-dystroglycans that binds to the extracellular matrix protein laminin. Dystrophin mutations resulting in truncated dystrophin proteins unable to bind to the membrane cause progressive muscle degeneration and atrophy (Xu L. et al., 2021). The unconventional myosins Myo1e and Myo1f are motor ABPs that can connect the actin cytoskeleton with the plasma membrane via transmembrane Fcγ receptors (FcR) in macrophages to control membrane tension during FcR-mediated phagocytosis (Barger et al., 2019). Absence of both myosins significantly impairs actin-dependent phagocytic cup formation and clearance of pathogens. Myo1e is also important for actin polymerization and integrin clustering in neutrophils during extravasation (Vadillo et al., 2019). These are only a few examples highlighting the important cell biological functions of ABPs in different pathophysiological contexts. With newly identified biochemical and biological properties of ABPs, they have been considered as important Edited and reviewed by: Akihiko Ito, Kindai University, Japan


INTRODUCTION
Actin is an essential cytoskeletal protein that provides structural support for multiple cellular processes including cellular motility, division and contractility (Pollard and Goldman, 2018). Actin filaments exist in association with binding partners, mainly actin-binding proteins (ABPs) that together control the many functions of the actin cytoskeleton (Lehman and Maeda, 2020). ABPs can bind actin monomers, polymers or both and more than 160 ABPs have been identified to date (Winder and Ayscough, 2005). However, classification of ABPs is difficult because actin binding is a common process, but can result in a plethora of different functional outcomes. Therefore, attempts to classify ABPs has left many "orphans" that do not fit into families (dos Remedios et al., 2003). Generally, ABPs can be divided into two broad categories, depending on their effect on actin filament dynamics (Stehn et al., 2006). The first category of ABPs regulates the G-actin/F-actin turnover thus controlling cytoskeletal responses to external stimuli. This category includes Arp2/3, ADF/cofilin, profilin, gelsolin, etc (Stehn et al., 2006). The second general category of ABPs helps actin filamnets to form higher order structures, such as actin filaments meshworks or bundles. This category includes tropomyosin, caldesmon, filamin, dystrophin, among others (Stehn et al., 2006).
ABPs also link actin filaments to the plasma membrane, thus facilitating outside-in and inside-out signaling ( Figure 1). For example, dystrophin anchors the actin cytoskeleton to membrane glycoproteins such as β-dystroglycans that binds to the extracellular matrix protein laminin. Dystrophin mutations resulting in truncated dystrophin proteins unable to bind to the membrane cause progressive muscle degeneration and atrophy (Xu L. et al., 2021). The unconventional myosins Myo1e and Myo1f are motor ABPs that can connect the actin cytoskeleton with the plasma membrane via transmembrane Fcγ receptors (FcR) in macrophages to control membrane tension during FcR-mediated phagocytosis (Barger et al., 2019). Absence of both myosins significantly impairs actin-dependent phagocytic cup formation and clearance of pathogens. Myo1e is also important for actin polymerization and integrin clustering in neutrophils during extravasation (Vadillo et al., 2019). These are only a few examples highlighting the important cell biological functions of ABPs in different pathophysiological contexts. With newly identified biochemical and biological properties of ABPs, they have been considered as important targets in treating diseases (Yin et al., 2018b;Vadillo et al., 2019;Yin et al., 2019). This special issue contains 31 original and review papers, that discuss the recent advances in our knowledge about ABPs and their various biological processes. These studies also highlight new avenues for future ABPs research.
Profilin and the actin-related protein 2/3 (Arp2/3) complex are key regulators of actin polymerization and branched actin networks, respectively. Pandey and Chaudhary review the evolution of the profilin gene family in plants, discussing that profilins play important roles in both cytoskeleton maintenance and plant development (Pandey and Chaudhary). Murk et al.  Xu et al. show that changes in cofilin-1 expression appear at the same time as gait imbalance suggesting that it may affect motor cortex function (Xu et al.). Xu et al. review the structural features, phosphorylation patterns and functions of cofilin in regulating cancer metastasis and apoptosis, highlighting that cofilin may be a therapeutic target for treating cancers (Xu et al.).
Three transgelin isoforms exist that are named for their potential to induce actin gelation (Yin et al., 2019).

CONCLUSION AND FUTURE PERSPECTIVE
With the help of ABPs, actin filaments can be assembled, elongated, branched, disassembled and formed into dynamic networks as response to extracellular stimuli (Tang, 2018). As ABPs are essential for actin filament dynamics, they are closely related to various human diseases. Several drugs targeting ABPs (e.g. dystrophin, tropomyosin, troponin, etc) have been developed to treat disorders related to actin or myosin dysfunctions, many of which have been approved by the FDA. For example, the antisense oligonucleotide Vyondys 53 has been approved for the treatment of Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 53 skipping (Frank et al., 2020). Levosimendan targets troponin C for treating low cardiac output syndrome after cardiac surgery is being tested in phase III trials (Pollesello et al., 2019). These are only two recent examples and numerous other clinical trials testing new ABP-targeting compounds have been launched. Despite their potential, there is certainly more room for testing ABPs as targets in different diseases because they are ubiquitously expressed and involved in many different crucial cellular functions. In this respect, this special issue provides timely research and scholar overviews that shed new light on ABP functions in health and disease. We hope our efforts will help researchers to acquire a better understanding of ABPs.

AUTHOR CONTRIBUTIONS
L-MY designed the work, wrote the manuscript and prepared the figure. MS and C-DJ drafted and revised the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

FUNDING
This work was supported by National Natural Science Foundation of China (No. 81922076, 81873373).