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Accelerating on a Treadmill: ADF/Cofilin Promotes Rapid Actin Filament Turnover in the Dynamic Cytoskeleton Julie A

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Accelerating on a Treadmill: ADF/Cofilin Promotes Rapid Actin Filament Turnover in the Dynamic Cytoskeleton Julie A Mini-Review Accelerating on a Treadmill: ADF/Cofilin Promotes Rapid Actin Filament Turnover in the Dynamic Cytoskeleton Julie A. Theriot Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02160 ctin is among the most thoroughly studied of pro- (for review see 16). ADF/cofilin is an essential protein in teins. It was first identified half a century ago as all species where its necessity has been tested genetically. A the major component of thin filaments in muscle. Unusual among actin-binding proteins, members of this Work in the 1960s and 1970s showed that actin is also family bind in a 1:1 stoichiometry to actin in both mono- present in nonmuscle cells as well as in plants and proto- meric and filamentous forms, and they induce rapid depo- zoa. The actin-based cytoskeleton appears to be ubiqui- lymerization of actin filaments, which is enhanced at ele- tous among eukaryotes, and indeed the invention of the vated pH . The actin-binding activities of various members actin cytoskeleton may have been a key step in the earliest of the ADF/cofilin family are inhibited by phosphoryla- history of the eukaryotic lineage. A densely written sum- tion and/or by competitive binding of phosphoinositides; mary of the most important known properties of actin fills thus ADF/cofilins are good candidates for downstream ef- a good-sized volume (23). But there are major discrepan- fectors of several types of signaling cascades that cause re- cies between the well-characterized in vitro behavior of arrangements of the actin cytoskeleton. Consistent with a purified actin and the apparent behavior of actin filaments role in rapid filament turnover inside the cell, ADF/cofilin inside of intact, living cells. is typically concentrated at the dynamic actin-rich lamelli- Two discrepancies have been particularly puzzling. First, podium in locomoting cells. Members of this class of actin- the concentration of unpolymerized actin present in most binding proteins have recently been receiving increasing vertebrate nonmuscle cells is z100-fold higher than the attention from investigators interested in cytoskeletal dy- concentration of monomeric actin that can exist at steady namics. Since an excellent and comprehensive review on state in vitro (for review see 5). Second, the apparent rate the properties of this protein family was published a little of turnover of actin filaments in dynamic structures inside over a year ago (16), several interesting new findings have living cells is up to 100 times faster than can be accounted been reported that greatly enhance our understanding of for by the in vitro turnover kinetics (for review see 28). the roles of ADF/cofilin in regulating the actin cytoskele- The first puzzle has been solved by the recent identifica- ton in living cells. In this brief review, I will concentrate tion of abundant small actin monomer-binding peptides, primarily on these new findings. thymosin b4 and its close relatives, that sequester much of the actin monomer inside cells (for review see 17). The so- Actin Filament Dynamics and Treadmilling Are lution to the second puzzle may also lie with an actin-bind- Enhanced by ADF/Cofilin ing protein. Two articles in this issue of The Journal of Cell Actin monomers polymerize in a head-to-tail fashion to Biology (3, 21) lend support to the hypothesis that the form long helical filaments whose two ends are structur- rapid turnover of actin filaments inside living cells is ally and dynamically distinct. The on- and off-rates of actin largely promoted by a group of small (15–22 kD) actin- subunit addition to one end, the barbed end, are substan- binding proteins that includes cofilin, destrin, depactin, ac- 1 tially faster than the equivalent rates at the opposite end, tophorin, and actin depolymerizing factor (ADF) , collec- the pointed end. The concentration of actin monomer tively called the ADF/cofilin family. where the on- and off-rates are balanced is called the criti- Like actin itself, ADF/cofilin family members are found cal concentration. Actin is an ATPase, and ATP is rapidly in all eukaryotes including mammals, birds, amphibians, hydrolyzed after polymerization. Due to this constant en- flies, worms, echinoderms, plants, fungi, and protozoans ergy consumption, the actin polymer exhibits several inter- esting nonequilibrium behaviors; most notably, it is able to maintain different critical concentrations at the two ends Please address all correspondence to Julie A. Theriot, Whitehead Institute (19). At an intermediate actin monomer concentration, it for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02160. is possible to reach a steady state where monomer associ- Tel.: (617) 258-6036. Fax: (617) 258-7226. e-mail: [email protected] ates at the barbed end at the same rate as monomer disso- 1. Abbreviation used in this paper: ADF, actin depolymerizing factor. ciates from the pointed end. This results in a steady-state The Rockefeller University Press, 0021-9525/97/03/1165/4 $2.00 The Journal of Cell Biology, Volume 136, Number 6, March 24, 1997 1165–1168 1165 flux of subunits through the filament, generally termed drolysis by actin to enhance filament treadmilling could be treadmilling. The rate of actin filament treadmilling is lim- provided by an examination of ADF/cofilin effects on dy- ited by the off-rate of ADP-actin monomers at the pointed namics at the barbed end of filaments prepared from ADP- end. Since actin filament turnover inside living cells occurs actin. ADP-actin is a true equilibrium polymer where the up to two orders of magnitude faster than can be ac- critical concentrations must be identical at the two ends counted for by this off-rate (for review see 28), researchers (though the kinetics may still differ) (19). have long postulated the existence of a cellular factor that Some of the conclusions reached by Carlier et al. will be acts specifically to accelerate the pointed end off-rate and controversial. In particular, the suggestion that ADF1 en- therefore the rate of actin filament treadmilling. Until hances the on-rate of monomers at the filament barbed end now, no candidate factor had been shown to have this par- is difficult to reconcile with the observation that barbed- ticular activity. end elongation is a diffusion-limited reaction (4). It is hard In this issue of The Journal of Cell Biology, Carlier et al. to imagine how ADF binding to an actin monomer could (1997) demonstrate that ADF/cofilins can indeed perform increase the rate of its thermally driven collision with a fil- this function (3). They have used bacterially expressed ament end. The authors argue that the rate enhancement ADF1 from Arabidopsis thaliana and carefully examined might be due to an electrostatic effect, where ADF bind- its effects on the in vitro filament dynamics of rabbit skeletal ing enhances the dipole moment of the actin monomer in a muscle actin. Although plant ADF/cofilin family members way that steers the association reaction (3). Another possi- share only z30% amino acid identity with the vertebrate ble interpretation of the rate enhancements of both poly- family members (10, 11), their actin-binding and -depoly- merization and depolymerization is that ADF/cofilin in- merizing functions appear to be generally similar (11). Us- creases the number of filament ends present in the in vitro ing a series of kinetic methods designed to measure sepa- reactions by severing the actin filaments. However, in con- rately the effects of ADF1 on the association and dissociation trast with a number of earlier reports, Carlier et al. do not rates at the two ends of the actin filament, Carlier et al. find any evidence for ADF-induced actin filament sever- have found that ADF1 accelerates the on-rate of actin ing using either EM or analytical ultracentrifugation, and monomer at the barbed end by 12-fold, without noticeably their kinetic results are quantitatively inconsistent with a increasing the off-rate. At the pointed end, the on-rate is significant severing activity. Observations that have previ- modestly enhanced, while the off-rate is accelerated by ously been interpreted as evidence for severing by other z22-fold. Since actin filament treadmilling is limited by members of the ADF/cofilin family (including a rapid the pointed-end off-rate, we expect that ADF1 should ac- drop in pyrene-actin fluorescence and an acceleration of celerate the rate of treadmilling by approximately the same the initial phase of actin polymerization including “over- amount. Indeed, both the treadmilling rate (as measured shoot” kinetics) are also demonstrable using Arabidopsis by a pulse-chase experiment using fluorescently labeled ADF1, but they can be reinterpreted as effects due to the nucleotide) and the steady-state actin ATPase are speeded dramatic acceleration of the kinetics at the two ends of the up z25-fold in the presence of saturating ADF1 (3). In actin filament (3). On the other hand, severing activity has other words, the difference between the critical concentra- been directly observed by videomicroscopy for two ADF/ tions of the barbed and pointed ends is greatly enhanced cofilin family members, Acanthamoeba castellanii acto- by the presence of ADF. phorin (14) and human ADF (9), and the rapid drop in vis- These results suggest that the actin/ADF complex can cosity of actin filament solutions upon addition of ADF is be thought of as a second type of polymer, dynamically most consistent with a severing mechanism. At present, al- distinct from the pure actin polymer. This is quite different though it is clear that ADF/cofilin family members en- from the effects of factors such as thymosin b4 that en- hance filament disassembly in vitro, neither of the two courage actin filament depolymerization through seques- proposed mechanisms (filament severing vs acceleration tration of actin monomer; although sequestering factors of treadmilling) can satisfactorily explain all available data, can alter the final steady-state level of actin filaments, they nor are they mutually exclusive.
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