scholarly journals The Relative Binding Position of Nck and Grb2 Adaptors Dramatically Impacts Actin-Based Motility of Vaccinia Virus

2021 ◽  
Author(s):  
Angika Basant ◽  
Michael Way
Keyword(s):  
Vaccinia Virus ◽  
Binding Sites ◽  
Actin Polymerization ◽  
Cellular Processes ◽  
Viral Spread ◽  
Relative Binding ◽  
Signal Output ◽  
Signalling Cascade ◽  
Binding Position

ABSTRACTPhosphotyrosine (pTyr) motifs in unstructured polypeptides orchestrate important cellular processes by engaging SH2-containing adaptors to nucleate complex signalling networks. The concept of phase separation has recently changed our appreciation of such multivalent networks, however, the role of pTyr motif positioning in their function remains to be explored. We have now explored this parameter in the assembly and operation of the signalling cascade driving actin-based motility and spread of Vaccinia virus. This network involves two pTyr motifs in the viral protein A36 that recruit the adaptors Nck and Grb2 upstream of N-WASP and Arp2/3-mediated actin polymerization. We generated synthetic networks on Vaccinia by manipulating pTyr motifs in A36 and the unrelated p14 from Orthoreovirus. In contrast to predictions, we find that only specific spatial arrangements of Grb2 and Nck binding sites result in robust N-WASP recruitment, Arp2/3 driven actin polymerization and viral spread. Our results suggest that the relative position of pTyr adaptor binding sites is optimised for signal output. This finding may explain why the relative positions of pTyr motifs are usually conserved in proteins from widely different species. It also has important implications for regulation of physiological networks, including those that undergo phase transitions.

scholarly journals The WASP Homologue Las17 Activates the Novel Actin-regulatory Activity of Ysc84 to Promote Endocytosis in Yeast

2009 ◽  
Vol 20 (6) ◽  
pp. 1618-1628 ◽  
Author(s):  
Alastair S. Robertson ◽  
Ellen G. Allwood ◽  
Adam P.C. Smith ◽  
Fiona C. Gardiner ◽  
Rosaria Costa ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Actin Polymerization ◽  
Actin Binding ◽  
The Novel ◽  
Cellular Processes ◽  
New Class ◽  
Actin Binding Domain ◽  
Kinetics Of ◽  
Actin Binding Site

Actin plays an essential role in many eukaryotic cellular processes, including motility, generation of polarity, and membrane trafficking. Actin function in these roles is regulated by association with proteins that affect its polymerization state, dynamics, and organization. Numerous proteins have been shown to localize with cortical patches of yeast actin during endocytosis, but the role of many of these proteins remains poorly understood. Here, we reveal that the yeast protein Ysc84 represents a new class of actin-binding proteins, conserved from yeast to humans. It contains a novel N-terminal actin-binding domain termed Ysc84 actin binding (YAB), which can bind and bundle actin filaments. Intriguingly, full-length Ysc84 alone does not bind to actin, but binding can be activated by a specific motif within the polyproline region of the yeast WASP homologue Las17. We also identify a new monomeric actin-binding site on Las17. Together, the polyproline region of Las17 and Ysc84 can promote actin polymerization. Using live cell imaging, kinetics of assembly and disassembly of proteins at the endocytic site were analyzed and reveal that loss of Ysc84 and its homologue Lsb3 decrease inward movement of vesicles consistent with a role in actin polymerization during endocytosis.

scholarly journals In guinea pig sperm, aldolase A forms a complex with actin, WAS, and Arp2/3 that plays a role in actin polymerization

Reproduction ◽  
2009 ◽  
Vol 137 (4) ◽  
pp. 669-678 ◽  
Author(s):  
Natalia Chiquete-Felix ◽  
José Manuel Hernández ◽  
J Alfredo Méndez ◽  
Armando Zepeda-Bastida ◽  
Alicia Chagolla-López ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Energy Production ◽  
Actin Polymerization ◽  
Glycolytic Enzymes ◽  
Cellular Processes ◽  
Aldolase A

Glycolytic enzymes have, in addition to their role in energy production, other functions in the regulation of cellular processes. Aldolase A has been reported to be present in sperm, playing a key role in glycolysis; however, despite its reported interactions with actin and WAS, little is known about a non-glycolytic role of aldolase A in sperm. Here, we show that in guinea pig spermatozoa, aldolase A is tightly associated to cytoskeletal structures where it interacts with actin, WAS, and Arp2/3. We show that aldolase A spermatozoa treatment increases their polymerized actin levels. In addition, we show that there is a direct correlation between the levels of polymerized actin and the levels of aldolase A–actin interaction. Our results suggest that aldolase A functions as a bridge between filaments of actin and the actin-polymerizing machinery.

scholarly journals Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Baoyu Chen ◽  
Hui-Ting Chou ◽  
Chad A Brautigam ◽  
Wenmin Xing ◽  
Sheng Yang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Binding Sites ◽  
Actin Polymerization ◽  
Rho Gtpase ◽  
Biochemical Data ◽  
Actin Assembly ◽  
Cellular Processes ◽  
Cryo Electron Microscopy ◽  
Regulatory Complex ◽  
Rac1 Gtpase

The Rho GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization, which underpins diverse cellular processes. Here we report the structure of a WRC-Rac1 complex determined by cryo-electron microscopy. Surprisingly, Rac1 is not located at the binding site on the Sra1 subunit of the WRC previously identified by mutagenesis and biochemical data. Rather, it binds to a distinct, conserved site on the opposite end of Sra1. Biophysical and biochemical data on WRC mutants confirm that Rac1 binds to both sites, with the newly identified site having higher affinity and both sites required for WRC activation. Our data reveal that the WRC is activated by simultaneous engagement of two Rac1 molecules, suggesting a mechanism by which cells may sense the density of active Rac1 at membranes to precisely control actin assembly.

scholarly journals The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry

2012 ◽  
Vol 23 (12) ◽  
pp. 2253-2263 ◽  
Author(s):  
Mónica Gordón-Alonso ◽  
Vera Rocha-Perugini ◽  
Susana Álvarez ◽  
Olga Moreno-Gonzalo ◽  
Ángeles Ursa ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Adaptor Protein ◽  
Viral Receptor ◽  
Actin Remodeling ◽  
Cellular Processes ◽  
Immunodeficiency Virus ◽  
Viral Nucleocapsid ◽  
Hiv 1

Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4+T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP2) production, which are needed for successful HIV infection. We show that syntenin-1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV-1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP2accumulation is increased in syntenin-1–depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP2production, and the dynamics of HIV-1 entry.

scholarly journals Endocytic vacuole formation by WASH-mediated endocytosis

2021 ◽  
Author(s):  
Pia Brinkert ◽  
Lena Krebs ◽  
Pilar Samperio Ventayol ◽  
Lilo Greune ◽  
Carina Bannach ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Actin Polymerization ◽  
Endocytic Pathway ◽  
Vacuole Formation ◽  
Cellular Processes ◽  
Human Papillomavirus Type 16 ◽  
Systematic Perturbation ◽  
Membrane Bending ◽  
Endocytic Pathways

Endocytosis of extracellular or plasma membrane material is a fundamental process. A variety of endocytic pathways exist, several of which are barely understood in terms of mechanistic execution and biological function. Importantly, some mechanisms have been identified and characterized by following virus internalization into cells. This includes a novel endocytic pathway exploited by human papillomavirus type 16 (HPV16). However, its cellular role and mechanism of endocytic vacuole formation remain unclear. Here, HPV16 was used as a tool to examine the mechanistic execution of vesicle formation by combining systematic perturbation of cellular processes with electron and video microscopy. Our results indicate cargo uptake by uncoated, inward-budding pits facilitated by the membrane bending retromer protein SNX2. Actin polymerization-driven vesicle scission is promoted by WASH, an actin regulator typically not found at the plasma membrane. Uncovering a novel role of WASH in endocytosis, we propose to term the new pathway WASH-mediated endocytosis (WASH-ME).

scholarly journals Septins suppress the release of vaccinia virus from infected cells

2018 ◽  
Vol 217 (8) ◽  
pp. 2911-2929 ◽  
Author(s):  
Julia Pfanzelter ◽  
Serge Mostowy ◽  
Michael Way
Keyword(s):  
Plasma Membrane ◽  
Vaccinia Virus ◽  
Membrane Trafficking ◽  
Live Cell Imaging ◽  
Actin Polymerization ◽  
Antiviral Effect ◽  
Cellular Processes ◽  
Viral Egress ◽  
Infected Cells ◽  
Cell Spread

Septins are conserved components of the cytoskeleton that play important roles in many fundamental cellular processes including division, migration, and membrane trafficking. Septins can also inhibit bacterial infection by forming cage-like structures around pathogens such as Shigella. We found that septins are recruited to vaccinia virus immediately after its fusion with the plasma membrane during viral egress. RNA interference–mediated depletion of septins increases virus release and cell-to-cell spread, as well as actin tail formation. Live cell imaging reveals that septins are displaced from the virus when it induces actin polymerization. Septin loss, however, depends on the recruitment of the SH2/SH3 adaptor Nck, but not the activity of the Arp2/3 complex. Moreover, it is the recruitment of dynamin by the third Nck SH3 domain that displaces septins from the virus in a formin-dependent fashion. Our study demonstrates that septins suppress vaccinia release by “entrapping” the virus at the plasma membrane. This antiviral effect is overcome by dynamin together with formin-mediated actin polymerization.

The Actin Regulator Coronin-1A Modulates Platelet Shape Change and Consolidates Arterial Thrombosis

2018 ◽  
Vol 118 (12) ◽  
pp. 2098-2111 ◽  
Author(s):  
Thomas Stocker ◽  
Joachim Pircher ◽  
Artid Skenderi ◽  
Andreas Ehrlich ◽  
Clemens Eberle ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Actin Polymerization ◽  
Thrombus Formation ◽  
Shape Change ◽  
Actin Binding ◽  
Cellular Processes ◽  
Reduced Density ◽  
Induced Aggregation ◽  
Platelet Shape

AbstractCoronin-1A (Coro1A) belongs to a family of highly conserved actin-binding proteins that regulate cytoskeletal re-arrangement. In mammalians, Coro1A expression is most abundant in the haematopoietic lineage, where it regulates various cellular processes. The role of Coro1A in platelets has been previously unknown. Here, we identified Coro1A in human and mouse platelets. Genetic absence of Coro1A in mouse platelets inhibited agonist-induced actin polymerization and altered cofilin phosphoregulation, leading to a reduction in spreading and low-dose collagen induced aggregation. Furthermore, Coro1A-deficient mice displayed a defect in ferric chloride-induced arterial thrombosis with prolonged thrombus formation and reduced thrombus size. Immunofluorescence analysis revealed a less compact thrombus structure with reduced density of platelets and fibrinogen. In summary, Coro1A has a role in platelet biology with impact on spreading, aggregation and thrombosis.

scholarly journals Role of Changes in State of Bound Water and Tissue Stiffness in Development of Age-Related Diseases

Polymers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1362
Author(s):  
Garry Kerch
Keyword(s):  
Water Content ◽  
Actin Polymerization ◽  
Bound Water ◽  
Biological Tissues ◽  
Published Data ◽  
Tissue Stiffness ◽  
Cellular Processes ◽  
Age Related ◽  
Bound Water Content

An essential effect of environmental stiffness on biological processes in cells at present is generally accepted. An increase in arterial stiffness with advanced age has been reported in many publications. The aim of the present review is to summarize current information about possible chemical reactions and physical processes that lead to tissue stiffening and result in age-related diseases in order to find methods that can prevent or retard time-dependent tissue stiffening. The analysis of published data shows that bound water acts as a plasticizer of biological tissues, a decrease in bound water content results in an increase in biological tissue stiffness, and increased tissue stiffness leads to NF-kB activation and triggered actin polymerization—NF-kB activation is associated with age-related diseases. It can be suggested that changes in bound water content through changing tissue stiffness can affect cellular processes and the development of pathologies related to aging. Both age-related diseases and COVID-19 may be associated with tight-junction disruption and increased tissue stiffness and permeability.

Dysregulation of HOX as a Potential Therapeutic Target in Breast Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ji-Yeon Lee ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Hox Genes ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Genome Structure ◽  
Control Cell ◽  
Three Dimensional ◽  
Cellular Processes ◽  
Hox Protein

: HOX genes belong to the highly conserved homeobox superfamily, responsible for the regulation of various cellular processes that control cell homeostasis, from embryogenesis to carcinogenesis. The abnormal expression of HOX genes is observed in various cancers, including breast cancer; they act as oncogenes or as suppressors of cancer, according to context. In this review, we analyze HOX gene expression patterns in breast cancer and examine their relationship, based on the three-dimensional genome structure of the HOX locus. The presence of non-coding RNAs, embedded within the HOX cluster, and the role of these molecules in breast cancer have been reviewed. We further evaluate the characteristic activity of HOX protein in breast cancer and its therapeutic potential.

MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

2020 ◽  
Vol 26 ◽  
Author(s):  
Yini Ma ◽  
Xiu Cao ◽  
Guojuan Shi ◽  
Tianlu Shi
Keyword(s):  
Digestive System ◽  
Target Genes ◽  
Malignant Neoplasm ◽  
Vital Role ◽  
Diagnostic Biomarkers ◽  
Cellular Processes ◽  
Promising Therapeutic Target ◽  
Direct Target ◽  
Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

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