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• W2011565369 abstract "A clever genetic trick allows the lipid composition of the plasma membrane to be manipulated using light, paving the way for new investigations into the many membrane interactions that dictate cell shape, movement and communication. A clever genetic trick allows the lipid composition of the plasma membrane to be manipulated using light, paving the way for new investigations into the many membrane interactions that dictate cell shape, movement and communication. Many of the crucial cellular functions occurring at the plasma membrane rely on a small family of phosphorylated lipids, the phosphoinositides. These molecules direct the interactions and activities of a multitude of proteins at the membrane, impacting on many aspects of cellular physiology, from cell division to secretion. Recently, novel ‘optogenetic’ tools have been developed allowing manipulation of these lipids in living cells that is rapid, reversible and spatially restricted [1Idevall-Hagren O. Dickson E.J. Hille B. Toomre D.K. de Camilli P. Optogenetic control of phosphoinositide metabolism.Proc. Natl. Acad Sci. USA. 2012; 109: E2316-E2323Crossref PubMed Scopus (218) Google Scholar], facilitating investigations into the lipids' function with unprecedented temporal and spatial resolution. Indeed, the authors provide some fascinating new insights into the speed with which the lipids can modulate the underlying cytoskeleton. As the ultimate cellular frontier, the plasma membrane regulates the passage of ions and small molecules, dispatches and receives the vesicular carriers that import and export cargo, and bristles with receptors that relay signals from the environment or the rest of the organism. Crucial to all of these functions are proteins; some embedded within the membrane, such as the channels that carry potassium ions, while others are recruited to the membrane bilayer's inner leaflet, like the adaptor proteins that grab laden cargo receptors, sculpting the surrounding membrane into endocytic vesicles. Many of these proteins require interactions with phosphoinositide lipids, which either activate embedded membrane proteins (like ion channels), or act as an anchor for the recruitment of soluble proteins to the membrane surface (such as endocytic proteins). Historically, evidence for the participation of phosphoinositides in biological function came from biochemical and pharmacological studies of the lipids' metabolism, in vitro studies of protein–lipid interactions, and genetic studies of the kinases and phosphatases that make and degrade them. However, these studies are limited in their capacity to answer crucial questions about the kinetics and specificity of the functional interactions as they occur in living cells. The development of fluorescent biosensors permitted real-time readouts of phosphoinositide dynamics, but experimental manipulation still required either non-specific pharmacological manipulations, or else chronic genetic manipulations such as over-expression or knock-down of an enzyme. In the last decade, real-time manipulation of phosphoinositide function has become a reality using ‘chemical genetics’ — the manipulation of protein function using small, cell permeable drugs. Specifically, several groups independently devised a similar technique, which relies on the drug-induced heterodimerization of two proteins [2Várnai P. Thyagarajan B. Rohacs T. Balla T. Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells.J. Cell Biol. 2006; 175: 377-382Crossref PubMed Scopus (277) Google Scholar, 3Fili N. Calleja V. Woscholski R. Parker P.J. Larijani B. Compartmental signal modulation: Endosomal phosphatidylinositol 3-phosphate controls endosome morphology and selective cargo sorting.Proc. Natl. Acad. Sci. USA. 2006; 103: 15473-15478Crossref PubMed Scopus (81) Google Scholar, 4Heo W.D. Inoue T. Park W.S. Kim M.L. Park B.O. Wandless T.J. Meyer T. PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane.Science. 2006; 314: 1458-1461Crossref PubMed Scopus (539) Google Scholar, 5Suh B.-C. Inoue T. Meyer T. Hille B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels.Science. 2006; 314: 1454-1457Crossref PubMed Scopus (405) Google Scholar]. One of these proteins is fused to a membrane-targeting motif, often a small plasma membrane-bound peptide. The other is fused to a phosphoinositide-modifying enzyme, stripped of its regulatory domains so that the catalytic core is adrift in the cytoplasm, away from its substrate. On addition of the dimerizing drug, the two proteins dimerize and the enzyme is recruited to its target membrane (Figure 1A). This can lead within seconds to degradation of the phosphoinositide target, such as the dually phosphorylated lipid PIP2 after recruitment of a phosphatase activity. The system can also be used to elevate lipid concentration, for example by recruitment of a PI 3-kinase that converts PIP2 to tris-phosphorylated PIP3. When coupled to a real-time readout of cellular function, the role of the lipid can thus be interrogated in vivo. Such studies have already demonstrated the crucial roles of PIP2 in ion channel activity [5Suh B.-C. Inoue T. Meyer T. Hille B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels.Science. 2006; 314: 1454-1457Crossref PubMed Scopus (405) Google Scholar], clathrin-mediated endocytosis and the recruitment of F-actin nucleating complexes [2Várnai P. Thyagarajan B. Rohacs T. Balla T. Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells.J. Cell Biol. 2006; 175: 377-382Crossref PubMed Scopus (277) Google Scholar, 6Zoncu R. Perera R.M. Sebastian R. Nakatsu F. Chen H. Balla T. Ayala G. Toomre D. De Camilli P.V. Loss of endocytic clathrin-coated pits upon acute depletion of phosphatidylinositol 4,5-bisphosphate.Proc. Natl. Acad. Sci. USA. 2007; 104: 3793-3798Crossref PubMed Scopus (206) Google Scholar], to name but a few examples. Although a revolutionary advance, these methods still carry some drawbacks. Firstly, the induced interaction is high affinity, so dimerization is essentially irreversible over the time-course of an experiment. Secondly, because the targeting motif is found throughout its host membrane, recruitment of the enzyme occurs over the entire membrane compartment. This makes it difficult to investigate localized roles for phosphoinositides in membranes, such as at the cleavage furrow during cytokinesis or at the leading edge of motile cells [7Saarikangas J. Zhao H. Lappalainen P. Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides.Physiol. Rev. 2010; 90: 259Crossref PubMed Scopus (367) Google Scholar]. This is where the new ‘optogenetic’ technology comes in [8Kennedy M.J. Hughes R.M. Peteya L.A. Schwartz J.W. Ehlers M.D. Tucker C.L. Rapid blue-light-mediated induction of protein interactions in living cells.Nat. Methods. 2010; 7: 973-975Crossref PubMed Scopus (757) Google Scholar]. Relying on the same principle of induced dimerization as for the chemical genetic systems described above, this method instead uses a light-sensitive CRY2 cryptochrome domain. Upon irradiation with blue light, CRY2 undergoes a conformational shift, allowing binding to the membrane-targeted CIBN domain (Figure 1B). The interaction occurs faster than chemical-induced dimerization — the blue light traverses the medium and plasma membrane somewhat faster than a chemical activator diffuses! — but crucially, using common laser-scanning confocal and ‘TIRF’ microscopes, the blue light can be easily targeted to micron scale regions of the cell. The light-activated CRY2 domain is therefore only recruited to the proximal membrane that it first encounters by diffusion. Phosphoinositide–protein interactions typically occur over a timescale of seconds, and the lipids themselves take minutes to diffuse through the membrane from one end of the cell to the other, meaning phosphoinositide pools often act over micron-scale distances [9Hammond G.R.V. Sim Y. Lagnado L. Irvine R.F. Reversible binding and rapid diffusion of proteins in complex with inositol lipids serves to coordinate free movement with spatial information.J. Cell Biol. 2009; 184: 297-308Crossref PubMed Scopus (66) Google Scholar, 10Teruel M.N. Meyer T. Translocation and reversible localization of signaling proteins: a dynamic future for signal transduction.Cell. 2000; 103: 181-184Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. Because the light-induced interaction between CRY2 and CIBN occurs in seconds and reverses over a timescale of minutes, the system works over a comparable scale to the lipids. This has allowed the authors to perform real-time manipulation of lipid function in a polarized fashion for the first time [1Idevall-Hagren O. Dickson E.J. Hille B. Toomre D.K. de Camilli P. Optogenetic control of phosphoinositide metabolism.Proc. Natl. Acad Sci. USA. 2012; 109: E2316-E2323Crossref PubMed Scopus (218) Google Scholar]. Idevall-Hagren et al. [1Idevall-Hagren O. Dickson E.J. Hille B. Toomre D.K. de Camilli P. Optogenetic control of phosphoinositide metabolism.Proc. Natl. Acad Sci. USA. 2012; 109: E2316-E2323Crossref PubMed Scopus (218) Google Scholar] began by recruiting a PIP2-degrading phosphatase to the entire plasma membrane, showing that it worked as effectively — indeed, faster — than chemically-induced recruitment of the enzyme, both in terms of stripping the membrane of PIP2 binding proteins, and of blocking potassium channel activity. However, several surprising findings were made when enzymes were recruited to confined regions of the plasma membrane. Local degradation of PIP2 often led to local retraction of the membrane, as might be expected due to localized detachment of the underlying F-actin cytoskeleton [11Raucher D. Stauffer T. Chen W. Shen K. Guo S. York J.D. Sheetz M.P. Meyer T. Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion.Cell. 2000; 100: 221-228Abstract Full Text Full Text PDF PubMed Scopus (583) Google Scholar]. But the authors also made two very unexpected observations. Firstly, in ‘spared’ regions of the membrane not subject to enzyme-induced PIP2 depletion, membrane ruffling was seen to occur, as if the F-actin modulators liberated from the site of PIP2 degradation were now acting in these spared regions. Secondly, when the dimerization-inducing blue light was shut off, and PIP2 levels began to recover, the affected membrane regions often ruffled and spread, as if new F-actin polymerization was being stimulated. Similarly, when PIP3 synthesis was induced locally in the plasma membrane, as well as stimulating membrane ruffling due to F-actin polymerization where the synthesis was occurring, ruffling was actually inhibited in other regions. Indeed, these phenomena could be reversed simply by redirecting the blue light to different regions of the cell. Such novel observations demonstrate that changes in phosphoinositide concentrations can have direct and immediate effects on the underlying F-actin cytoskeleton, with profound implications for the regulation of cell shape and motility. These tantalizing observations will no doubt spur many new studies and insights into the regulation of cell physiology by phosphoinositides. Other technical advances are still required, particularly in terms of more potent and specific pharmacological inhibitors of the lipid-modifying enzymes; these will be both valuable experimental tools, as well as potential therapies for the many diseases associated with phosphoinositide malfunction. Nevertheless, the utility of these new optogenetic tools provides the exciting opportunity to explore the roles of these lipids in polarized cellular activities, both in isolated cells and perhaps whole organisms." @default.
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• W2011565369 title "Membrane Biology: Making Light Work of Lipids" @default.
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