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Review
. 2020 Mar 10;9(3):672.
doi: 10.3390/cells9030672.

Yeast as a Model to Understand Actin-Mediated Cellular Functions in Mammals-Illustrated with Four Actin Cytoskeleton Proteins

Zain Akram  1 , Ishtiaq Ahmed  1 , Heike Mack  1 , Ramandeep Kaur  2 , Richard C Silva  3 , Beatriz A Castilho  4 , Sylvie Friant  2 , Evelyn Sattlegger  5 , Alan L Munn  1
Affiliations
Review

Yeast as a Model to Understand Actin-Mediated Cellular Functions in Mammals-Illustrated with Four Actin Cytoskeleton Proteins

Zain Akram et al. Cells. .

Abstract

The budding yeast Saccharomyces cerevisiae has an actin cytoskeleton that comprises a set of protein components analogous to those found in the actin cytoskeletons of higher eukaryotes. Furthermore, the actin cytoskeletons of S. cerevisiae and of higher eukaryotes have some similar physiological roles. The genetic tractability of budding yeast and the availability of a stable haploid cell type facilitates the application of molecular genetic approaches to assign functions to the various actin cytoskeleton components. This has provided information that is in general complementary to that provided by studies of the equivalent proteins of higher eukaryotes and hence has enabled a more complete view of the role of these proteins. Several human functional homologues of yeast actin effectors are implicated in diseases. A better understanding of the molecular mechanisms underpinning the functions of these proteins is critical to develop improved therapeutic strategies. In this article we chose as examples four evolutionarily conserved proteins that associate with the actin cytoskeleton: 1) yeast Hof1p/mammalian PSTPIP1, 2) yeast Rvs167p/mammalian BIN1, 3) yeast eEF1A/eEF1A1 and eEF1A2 and 4) yeast Yih1p/mammalian IMPACT. We compare the knowledge on the functions of these actin cytoskeleton-associated proteins that has arisen from studies of their homologues in yeast with information that has been obtained from in vivo studies using live animals or in vitro studies using cultured animal cell lines.

Keywords: BAR domain; F-BAR domain; Myc; WASP; Wiskott-Aldrich Syndrome; cancer; cytokinesis; endocytosis; translation factors; tumor suppressor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Actin cytoskeleton rearrangement during the cell cycle (in haploid or diploid cells). (1) Mid G1 phase: In the cell cycle actin (patches and cables) polarization starts during the shift from mid-G1 (1) to late-G1 phase (2). (2) Late G1 phase: Cells choose a new (nascent) bud site and then actin patches start to polarize to this nascent bud site and actin cables orient towards this nascent bud site (N.B. the spatial relationship of the nascent bud site to the previous bud site differs in haploids and diploids). (3) S phase: Cortical actin patches cluster at the tip of the bud and actin cables in the mother cell are oriented towards the newly formed bud. (4) G2 phase: Actin patches remain polarized to the growing bud but are no longer clustered and become isotropic within the bud while actin cables in the mother cell remain oriented to the growing bud. (5) Mid M-phase (mitosis): Actin patches become completely depolarized throughout the mother cell and bud while maintaining localization around the cell cortex and actin cables are randomly oriented. (6) Late anaphase: Actin patches and cables are depolarized in the large bud and mother cell and actin is recruited to the Myo1p ring to form an actomyosin ring. (7) Telophase/Early G1: Actin patches are polarized and actin cables are oriented to the site of cell division in both the mother cell and bud and contraction of the actomyosin ring results in cytokinesis.
Figure 2
Figure 2
Schematic depicting the domain structure of Saccharomyces cerevisiae (Sc) Hof1p and Homo sapien (Hs) PSTPIP1. FCH domain: Fes CIP4 Homology domain, PEST motif: proline, glutamic acid, serine, threonine-rich motif, SH3 domain: Src Homology 3 domain.
Figure 3
Figure 3
Gcn2 and Yih1p/IMPACT activity is controlled via spatiotemporally constrained rearrangements of the actin cytoskeleton. (A) Interactions preventing Gcn2 activation and thus resulting in high rates of protein synthesis. In the current working model, eEF1A binds to Gcn2 to prevent its stimulation. Low G-actin levels dissociate Yih1/IMPACT from actin and Yih1/IMPACT then binds to Gcn1, thereby preventing Gcn1 from activating Gcn2. Current findings suggest that this is due to its inability to promote transfer of the starvation signal (uncharged tRNAs, i.e., tRNAdeacyl) to Gcn2. Yih1/IMPACT released from actin would allow Yih1/IMPACT to also execute Gcn2-independent functions. Increased de novo synthesis of eEF1A, and/or its augmented release from F-actin, enhances eEF1A binding to Gcn2 to prevent its activation. (B) Interactions promoting Gcn2 activation and eIF2α phosphorylation by Gcn2 to dampen global protein synthesis and enhance translation of specific mRNAs. Uncharged tRNAs (tRNAdeacyl) abrogate Gcn2-eEF1A interaction, allowing Gcn2 activation. Enhanced eEF1A interaction with F-actin may also favor dissociation of eEF1A from Gcn2. Actin depolymerization increases the levels of G-actin, which then sequesters Yih1/IMPACT. Sequestration of Yih1/IMPACT allows enhanced Gcn1-Gcn2 interaction, which in turn enhances Gcn2 sensitivity to tRNAdeacyl. Actin depolymerization leads to increased levels of tRNAdeacyl and this further contributes to the activation of Gcn2. Enhanced Gcn2 activity and eIF2α phosphorylation lead to attenuation of global protein synthesis and concomitant enhancement of the expression of Gcn4/ATF4. These major transcriptional regulators adjust the gene expression profile in response to the activating cue that was imposed on the cell. (C) Simple schematic showing the domains of Gcn1, Gcn2 and IMPACT and the protein regions known so far to be involved in protein-protein interactions that stimulate or inhibit Gcn2. For simplicity, the ribosome has been omitted in this figure and instead protein regions involved in interactions with the ribosome are shown with a cyan shadow.
Figure 4
Figure 4
The different domains present in amphiphysins. (A) The yeast amphiphysins Rvs161p and Rvs167p. (B) The BIN1 mRNA is composed of 20 exons, some being alternatively spliced to give the different isoforms of BIN1 (Uniprot ID O00499). Some isoforms share the same domains. In the central nervous system, there are 6 isoforms termed isoforms 1 to 6, resulting from alternative splicing, only the canonical isoform 1 is shown. The different domains present or not in amphiphysins are: BAR for BIN1/Amphiphysin/Rvs167; SH3, Src homology 3; PRD, proline-rich domain also termed CLAP for Clathrin-Associated Protein Binding domain, encoded by exons 13 to 16 and present in the brain- specific isoforms 1 to 6; PI for Phosphoinositide domain, encoded by exon 11 (previously annotated exon 10) and present in the muscle-specific isoforms 8 and 10, and in the BIN1 tumor isoform 11 (previously termed BIN1 + 12A).
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