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EDITORIAL
Year : 2014  |  Volume : 4  |  Issue : 2  |  Page : 77-80

Spir ramps up the world of actin


Ph.D student from the Molecular Cell Biology Laboratory, Department of Neurology, University of Regensburg, Germany

Date of Web Publication29-Mar-2014

Correspondence Address:
Sreeja Lakshmi
Ph.D student from the Molecular Cell Biology Laboratory, Department of Neurology, University of Regensburg
Germany
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.129589

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How to cite this article:
Lakshmi S. Spir ramps up the world of actin. Int J Nutr Pharmacol Neurol Dis 2014;4:77-80

How to cite this URL:
Lakshmi S. Spir ramps up the world of actin. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2019 Nov 12];4:77-80. Available from: http://www.ijnpnd.com/text.asp?2014/4/2/77/129589

Cellular cytoskeleton, manned by the definite orchestration of actin filaments, microtubules, and intermediate filaments, accords the morphological dynamics and motility of the cells. Current research takes actin and it's interacting partners on par, placing actin cytoskeleton on the headline. Actin is a universal protein found in both prokaryotes and eukaryotes. [1] Under different stimuli, actin filaments get assembled to a multifarious cellular structures in order to cite the prominent cellular processes like muscle contraction, cell motility, cell division and cytokinesis, cell signaling and maintenance of cell junctions and cell shape, to name a few. [2],[3] To perform all these functions, the constitution of acin cytoskeleton need to be tightly regulated with the assistance of interacting partners, which control the polymerization of actin monomers to elicit actin filaments.


   Nucleation Machinery of Actin Cytoskeleton: Arp2/3, Formin, and Spir Top


The process of actin polymerization covers, initiation (initial association of acin monomers to form a dimer), nucleation (formation of a stable trimer), and elongation (rapid assembly of monomers). [4] Relative instability of polymerization intermediates (a dimer or trimer) and the abundance of actin monomer binding proteins, like profilin and β-thymosin in cells, supress the spontaneous actin polymerization. [5] Actin nucleation factors help to overcome the kinetic barrier to filament nucleation and elongation. [6],[7] Presently, three principal groups of actin nucleation factors are there. Arp 2/3 complex, the founding member of actin nucleation factors, composed of seven stably associated polypeptides including two name giving actin-related proteins Arp2 and Arp3, which together mimic as an actin dimer and serve as nucleation site. [8] In presence of nucleation promoting factors of Wiskott-Aldrich-Syndrome protein (WASp) superfamily, Arp 2/3 complex gets activated and elicits branched actin filaments, underpinning their presence in most crawling cells. [9] Formins are the second class, catalyzing nucleation as well as elongation of unbranched actin filaments with their unique and highly conserved formin homology 2 (FH2) domain flanked by proline rich FH1 domain. [10],[11] Fifteen distinct formins are found in mammals which are categorized into seven subfamilies. [12]

Following the buzz of Arp2/3 complex and formins into the world of actin polymerization, a new genre of nucleating proteins were launched that contain one or multiple actin binding WH2 (WASp homology 2) motifs, as their signature. They include Spir (4 WH2), [13] Cordon-Bleu (3 WH2), [14] leiomodin (1 WH2) [15] as well as bacterial nucleators-VopF/VopL (3 WH2) [16] and TARP (1 WH2). [17] Spir proteins are the primodial member of the emerging group of actin nucleation factors with tandem cluster of WH2 domains. In 2005, Quinlan et al.,[13] revealed a fillip to give a new lease on actin nucleation machinary catalyzed by Spir proteins, which were about to complete the trio of factors, along with Arp2/3 complex and formins. Spir gene was first identified in Drosophila melanogaster together with Capuccino (Capu), Drosophila formin, in a Drosophila screen to elucidate their requirement for proper development of oocytes and embryos. [18] Until now, the class of Spir proteins comprises-Drosophila Spir (dSpir), vertebrate -Spir-1 and Spir-2 proteins, the sea squirt Ciona Savignyi PEM-5 (posterior end mark-5), [19] and pEg6 of the African clawed frog Xenopus. [20] Spir-1 gene is expressed in developing nervous system in mouse embryos as well as in Purkinje cells of cerebellum, neuronal cells of hippocampus, and dentate gyrus, of adult mouse brain. Spir-1 was also detected in fetal liver and adult spleen. [21] Spir-2 gene possess broader expression pattern and is detected throughout the digestive tract, brain, testis, and kidney with no significant expression in spleen, lung, and liver. [22] Like formins, Spir induce unbranched, linear actin filaments [Figure 1]. [13],[5] Spir proteins form a well-conserved family in animals with single polypeptides having multiple domains starting from the N-terminus to C-terminus: Kinase non-catalytic C-lobe domain (KIND), a cluster of four WH2 domains, Spir box (SB) and FYVE domain. KIND is a protein interaction module of the protein, whereas WH2 domains are the actin-binding motifs and hence is the actin nucleation site. SB is related to a Rab GTPase-binding domain. [5] The sequence homology of SB is related to Rabphilin 3A which interact with Rab 3A GTPases. The Spir actin organizers are targeted to intracellular mambranes by their modified FYVE zinc finger domain to carry out the vesicle transport processes. [23],[24]
Figure 1: Mechanism of actin nucleation by Spir proteins: (a) The tandem WH2 domains are designated as A, B, C, and D, and the corresponding linker regions as L-1, L-2, and L-3. First two actin monomers get bound to WH2-D and WH2-C to initiate the formation of an actin dimer and are stabilized by L-3. Subsequently, G-actin is added to WH2-B and WH2-A to form trimer and tetramer. (b) Four actin monomers are bound to the cluster of four WH2 domains. (c) Further polymerization occurs at the barbed (+) end, whereas Spir proteins remain bound to the pointed end of the actin filament, (Adapted from Kerkhoff, 2006)

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   Physiological Functions of Spir: Synergy Among Spir and Formin Top


Formins are the prominent interaction partners of Spir. Direct Spir/formin interaction is well-studied in Drosophila[25] and recently in mammals [26] as well. In mammals, a Formin Spir Interaction (FSI) sequence at the very C-terminus of Fmn subgroup of formins and the KIND domain of Spir mediate the interaction. The interaction pattern was ascertained both by biochemical and X-ray crystallographic studies. [26],[27] The Spir/formin harmony unveils diverse physiological functions of Spir proteins.

Elucidation of Spir/formin cooperation began with the studies depicting requirement of dSpir and Capu proteins, to create and maintain the polarity of Drosophila oocytes, which prevents premature cytoplasmic streaming. Spir and Cappuccino mutant flies were found to be devoid of ooplasmic actin network, which in turn results in premature cytoplasmic streaming, loss of oocyte polarity and female sterility. [28],[29],[30] Likewise in Drosophila, a similar Fmn-2 dependent actin network was discovered in mouse oocytes, as an essential for the spindle relocation during asymmetric oocyte division. [31] Later on, progressive studies elucidated the cooperation of Fmn-2 with the mammalian Spir homologs, Spir-1 and Spir-2, in nucleating actin filaments in mouse oocytes. [32] Codepletion of Spir-1 and Spir-2 resulted in a tremendous reduction of F-actin in oocytes similar to the effect of latrunculin, an actin depolymerizing agent. This finding brings Spir-1 and Spir-2 forward as key elements in asymmetric oocyte division by mediating asymmetric spindle positioning through the development of actin network and polar body extrusion as they promote the assembly of the cleavage furrow. The mechanism of oocyte division is likely to be conserved among humans and mice as they share features like actin-dependent mechanism of asymmetric spindle positioning. [32]

In parallel to the pivotal role of Spir in Drosophila and mouse oogenesis, current research is heading to underpin the localization of Spir proteins. For the past 10 years, the Spir localization studies have seen many fruitful findings disclosing the function of the protein in vesicle transport processes. Membrane-binding property of Spir proteins depends on the integrity of C-terminus of the protein, comprising, the FYVE Zn-finger domain and SB lying N-terminal to FYVE domain. [23] FYVE domain is the cluster of basic amino acids between cysteines 2 and 3 of the consensus sequence, which recruite the proteins to the endosomal membrane by binding to phosphatidylinositol 3-phosphate. [33] The Spir zinc finger motif is a modified version of the FYVE domains (mFYVE), lacking the basic cluster between cysteines 2 and 3 and having a loop insertion between cysteines 6 and 7. [23] . FYVE domain is typical for the proteins with membrane trafficking property. [34] In Spir, FYVE domain enclosing eight potential zinc coordinating cysteines form a '`turret loop'` which helps in penetrating the membrane. [23] Either deletion of the SB or the mutation particularly at the turret loop of the FYVE domain leads to an even cytoplasmic distribution of the protein. [23] A previous study [35] uncovered the accumulation of Spir actin nucleators at the vesicle membranes of NIH 3T3 cells and subsequent induction of actin filaments. Spir proteins colocalize with the Rab11 GTPase, localized at the trans-Golgi network, post-Golgi vesicles, and the recycling endosome [23] , which assures the correlation between Spir and Rab11 which is involved in exocytosis and recycling processes. Overexpression of a mouse Spir-1 dominant interfering mutant inhibited the transport of the vesicular stomatitis virus G protein to the plasma membrane since the protein was arrested in membrane structures. [23] Localization of Spir-1 on early endosomes and induction of the formation of actin patches, was also found to depend on Annexin A2, a Ca2+-regulated phospholipid-binding and membrane binding proteins. [24] Even though the direct link between Spir and Annexin has not yet described, this finding leads to speculate that recruitment of Spir-1 to early endosomes via its FYVE domain is supported by Annexins. A recent study by Melina Schuh (2011) has shown that actin nucleation factors Spir-1, Spir-2, and Fmn2 elicits extensive actin network at Rab11a positive vesicles. The interconnection between the vesicles and their long range transportation to the cell membrane along the actin network is mediated by myosin Vb-dependent manner. [36]

It will be equally interesting to have an overview on the neurological functions of Spir proteins. The expression pattern of both the mammalian Spir homologs, Spir-1 and Spir-2 have been studied. Spir-1 is highly expressed in the developing nervous system and adult brain of mouse, which is highly overlapping with formin-2. Spir-2 was broadly expressed in adult mouse digestive tract, spermatocytes, and in the neuronal cells of the nervous system. [21],[22] Still, a close-grained study regarding the exact neuronal function of Spir proteins is yet to be disclosed in mammals. Nevertheless, a recent study in Drosophila[37] claims that overexpression of Spir is adversely affecting the axon growth in vivo similar to case, where Spir is lost. This points to the fact that a balanced actin dynamics is essential for effective neuronal morphogenesis. [37]


   Conclusion Top


Spir proteins are the primordial members of the emerging group of actin nucleation factors, initiating actin polymerization by binding monomeric actin through multiple WASp homology-2 domains. Studies to date unveiled the diverse cellular functions of Spir proteins in actin dynamics, Drosophila and mammalian oogenesis, vesicle trafficking, together with a kick-start in neuronal morphogenesis. Spir was unique in having its own way in actin nucleation by the tandem WH2 domains. Most of the physiological functions of Spir hinted toward its prominent interaction partner, formin. Both fly and mammalian oogenesis explains how critical is the harmony of Spir and formin in the maturation of oocytes, through the dynamic actin network. It carries importance to analyze whether the defects in Spir-1/Spir-2 and Fmn-2, leads to infertility or pregnancy loss in humans. The colocalization of Spir at the membranes of the Golgi apparatus suggest the role of Spir in vesicle trafficking than in leading edge motility. Despite the biological roles of Spir was interpreted to an extent in the fields of protein and membrane interactions, the exact mechanisms by which the protein is regulated will also pave a new direction of future research.

 
   References Top

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