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Arole of Cofilin/Destrin in Reorganization of Actin

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Arole of Cofilin/Destrin in Reorganization of Actin CELL STRUCTURE AND FUNCTION 21: 421-424 (1996) © 1996 by Japan Society for Cell Biology A Role of Cofilin/Destrin in Reorganization of Actin Cytoskeleton in Response to Stresses and Cell Stimuli Ichiro Yahara1, Hiroyuki Aizawa1, Kenji Moriyama1, Kazuko Iida1, Naoto Yonezawa3, Eisuke Nishida4, Hideki Hatanaka2, and Fuyuhiko Inagaki2 department of Cell Biology, ^Department of Molecular Physiology, The Tokyo Metropolitan Institute ofMedi- cal Science, Tokyo 113, *Department of Chemistry, Faculty of Science, Chiba University, Chiba 263, and insti- tute for Virus Research, Kyoto University, Kyoto 606-01 Key words: cofilin/actin/stress response/heat shock/nuclear translocation Various cellular events such as cell motility and divi- tyostelium discoideum (K.I. and H.A. , unpublished ob- sion are directed by the actin cytoskeleton under the con- servations). As will be seen below, phosphorylated cofi- trol of its regulatory system. Cofilin is a low molecular lin is inactive in the interaction with actin (3, 23, 24). weight actin-modulating protein that was originally iso- Thus it would be possible that growing cells of lower eu- lated from porcine brain (26) and is ubiquitously distri- caryotes might not need to inactivate cofilin whereas a buted in eucaryotes from the budding yeast to mam- portion of cofilin is always inactivated in resting cells of mals (4, 14, 21). Cofilin binds to actin in both monomer- higher eucaryotes. ic and polymerized forms in a 1:1 molar ratio and depo- In this review, we briefly summarize current progress lymerizes F-actin in a pH-dependent manner (26, 32). on research on structure and function of cofilin and dis- In vitro experiments indicated that cofilin binds and cuss a role(s) of cofilin in cellular responses. weakly severs F-actin at pH lower than 7.3 and depoly- merizes it at pH higher than 7.3. The pH-dependent, Cofilin is an Essential Actin-modulating Protein for functional alteration in cofilin may be physiologically LowerEucaryotes significant because cytosolic alkalization is induced Amongnumerousnumbers of actin-binding proteins upon cell stimulation by serum or growth factors (22) identified in S. cerevisiae, cofilin (14, 21) and MYO2-en- and acidification to pH 6.9 is induced upon heat shock coded unconventional myosin (15) are the only essential (9). Incubation of various cells in 5-10% DMSOor at el- proteins for yeast cells to be viable. The lethality caused evated temperatures induces destruction of actin cyto- by disruption of the yeast COF1gene is complemented skeleton and translocation of actin and cofilin to nuclei by the expression of porcine cofilin or destrin (14). The where they form rod-like structures (10, 12, 28). Al- structural and functional conservation of cofilin in low though a nuclear translocation signal sequence has been and higher eucaryotes suggests that cofilin is a key regu- identified in cofilin (1, 13, 19), stress-dependence of the latory protein of the actin cytoskeleton. In addition, D. translocation remains to be explained. discoideum has two cofilin genes, dCOFl and dCOF29 A body of evidence has indicated that a significant one of which, dCOF2is not expressed under any condi- portion of cofilin and/or destrin/ADF an isoprotein of tion and is therefore possibly a pseudogene. The disrup- cofilin, in mammalianand avian cells is phosphorylated tant of dCOFl has never been isolated although those at a serine residue(s) (8, 16, 29, 31). Upon heat shock of dCOF2were easily created, supporting the conclu- or treatment with DMSO,dephosphorylation of cofilin sion that dCOFl is an essential gene in this organism precedes the nuclear translocation of actin and cofilin (4). (29). In addition, dephosphorylation of cofilin and/or A yeast strain was created in which COF1is ex- destrin/ADF, has been detected upon stimulation of pressed under the GAL1promoter (K.I., unpublished various cell types including T-lymphocytes, platelets, as- observations). This strain is unable to grow in media trocytes, thyroid cells, parotid grand, and oocyte (2, 6, containing glucose or galactose as a sole carbon source 8, 16, 30, 31). These results strongly suggest that phos- but is able to normally grow in media containing mix- phorylation and dephosphorylation of cofilin and des- tures of the two sugars. This result strongly suggests trin/ADF are critical events that lead to reorganization that the overexpression of cofilin in yeast cells causes of the actin cytoskeleton and cell stimulation. Interest- cell arrest. Similar observations were also made by tran- ingly, phosphorylated cofilin was not detected in vegeta- sient transfection of cofilin CDNAin cultured mammali- tively growing cells of Saccharomyces cerevisiae or Die- an cells (K.I. and K.M., unpublished observations). Fur- 421 I. Yahara et al. thermore, microinjection of anti-Xenopus ADF/cofilin indicate that cofilin and ADF/destrin are reversibly inac- antibody or unphosphorylated Xenopus ADF/cofilin to tivated by phosphorylation. It should be noted, how- Xenopus embryos has been recently reported to inhibit ever, that phosphorylated cofilin binds PIP2 as does the cell division (2). All of these results suggest that appro- unphosphorylated form (24). priately controlled levels of active cofilin are required Phosphoamino acid analysis indicated that a serine for cell growth. residue(s) is phosphorylated in cofilin (3, 8, 16, 24, 29, 3 1). Peptide analysis of phosphorylated cofilin revealed Overexpression of Cofilin in Dictyostelium Cells that only the N-terminal peptide consisting of 21 amino Con focal microscopic dissection of D. discoideum acid residues is phosphorylated (24). This peptide con- cells immunofluorescently labeled with anti-cofilin anti- tains two serine residues, Ser-3 and Ser-8. These two bodies revealed that cofilin is codistributed with actin serine residues were separately replaced by Ala desig- on ruffling membranes but not on adhesion plaques (4). nated S3A and S8A mutants, respectively. S8A was This suggests that cofilin might be involved in dynamic phosphorylated but S3A was not when transfected to but not in static actin structures. To investigate further human293 cells. Onthe basis of these results, we con- functions of cofilin, biological phenotypes of D. disco- cluded that Ser-3 is the phosphorylation site of cofilin ideumcells in which the expression of Dictyostelium (24). This is consistent with the result by an other group cofilin (d-cofilin) was increased several fold were exam- on chicken ADF(3). ined (5). These cofilin-overexpressing cells were viable. S3D-cofilin may be structurally and functionally simi- The overexpression of cofilin caused co-overexpression lar to phosphorylated cofilin because both the mutated of actin in these cells. In addition, the amount of F-ac- cofilin and the phosphorylated protein possess negative tin but not of G-actin was increased in the overexpress- charges in the third amino acid residues. It was con- ing cells, suggesting that cofilin does not function in firmed that, like phosphorylated cofilin, S3D-cofilin vivo as a simpleactin-depolymerizingprotein or mono- does not bind to actin (24). Furthermore, the expression meric actin-sequestering protein. The overexpression of of S3D-cofilin was found not to rescue Acof1 yeast cells cofilin enhanced actin bundles as observed by fluores- whereas the wild type or S3A-cofilin did. This strongly cence microscopy. Consistent with this observation, it suggests that the ability of cofilin to bind to actin is cru- has also been reported that microinjenction or transient cial for the viability of yeast cells. overexpression of cofilin or ADF/destrin induced actin bundles in cultured mammalian cells (24, 25). Further- Identification and Structural Analysis of Actin-binding more, these cofilin-overexpressing cells exhibited en- Site of Cofilin hanced cell motility, indicating that cofilin is an up- Peptide mapping of cross-linked products of cofilin stream positive regulator of cell motility. and actin suggested that the region of cofilin containing It has been demonstrated that cofilin and its related Lys-112 and Lys-114 is involved in the binding to actin proteins have the activity to sever actin filaments (7, 17, (34). Indeed, a synthetic dodecapeptide corresponding 27). Actophorin, a homolog of cofilin in Acanthamoe- to the sequence from Trp-104 to Met-115 was found to ba, has been shown to transform latticework of actin fil- inhibit the binding of cofilin to G-actin (34). Similarly, aments cross-linked with a-actinin into bundles by sever- another peptide, DAIKKKL, corresponding to the se- ing the filaments (18). d-Cofilin was shown also to cause quence from Asp-122 to Leu-128 also weakly inhibited a similar transformation of actin structures (5). On the the binding to F-actin (33). basis of these results, it would be likely that the severing Recently, we determined the tertiary structure of des- activity rather than the monomericactin-sequestering trin/ADF, an isoprotein of cofilin, by triple-resonance activity is closely related to the in vivo function of cofi- multi-dimensional nuclear magneticresonance. It was lin. unexpectedly found that the folding of destrin is similar to those of repeated segments commonlypresent in the Negative Regulation of Cofilin by Phosphorylation on gelsolin family (1 1) although there are no amino acid se- Its Ser-3 Residue quence homologybetween these proteins. According to A mixture of phosphorylated and unphosphorylated the structure of gelsolin segment 1 and actin complex, cofilin was
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