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Nuclear actin andmyosins at a glance

Primal de Lanerolle

Department of Physiology and Biophysics,University of Illinois at Chicago, 835 South WolcottAvenue, Chicago, IL 60612, USA

primal@uic.edu

Journal of Cell Science 125, 4945–4949

� 2012. Published by The Company of Biologists Ltd

doi: 10.1242/jcs.099754

Actin and myosin II form the archetypical

molecular motor complex. Myosin II, like

all members of the myosin superfamily, is

an actin-activated ATPase that uses the

energy released when ATP is hydrolyzed to

do work. Although we typically associate

work with muscle contraction, cell motility

and cell division, many nuclear processes

require energy. Historically, the notion that

the nucleus contains actin or myosin has

been highly controversial. Because

filaments are central to the biological

functions of actin, this controversy was

fueled by the absence of actin or myosin

filaments in the nucleus. Nevertheless,

myosins I, II, V, VI, X, XVI and XVIII

have been described in the nucleus, and the

presence of actin in the nucleus is now

indisputable. However, it has been difficult

to recognize structures formed by nuclear

myosins and actin that are comparable to

actin–myosin structures found in the

cytoplasm. Because structure (or ‘form’) is

normally a guide to function in biology,

the absence of nuclear structures that are

obviously similar to those in the cytoplasm

has raised the possibility that nuclear

motors work in unique ways. This Cell

Science at a Glance article will review what

is known about actin and myosin in the

nucleus and how they differ in form and

function from their cytoplasmic counterparts.

Nuclear myosinsOne of the best examples of form following

function is the sarcomere, the basic

contractile unit of striated muscles. The

sliding of actin and myosin II organized

into filaments in sarcomeres, when ATP

is hydrolyzed, is the basis of muscle

contraction (Sellers, 2004). However, most

members of the myosin superfamily,

including nuclear myosin I and most of

the other myosins discovered in the nucleus,

do not form filaments (Sellers, 2004).

Although myosin II has been described in

the nucleus (Rodgers, 2005; Li and Sarna,

2009), myosin II filaments are yet to be

described in the nucleus. Nuclear myosin

Va is found in nuclear speckles, which are

(See poster insert)

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sites of RNA processing in transcriptionallyactive cells (Pranchevicius et al., 2008). By

contrast, myosin Vb interacts with actin andRNA polymerase I in nucleoli (Lindsayand McCaffrey, 2009). Myosin VI wasimplicated in transcription by RNA

polymerase II on the basis of chromatinimmunoprecipitation (ChIP) assays and theinhibition of transcription by antibodies

against myosin VI (Vreugde et al., 2006).Myosin X has also been identified in thenucleus by immunofluorescence, but its role

is not known (Woolner et al., 2008). MyosinXVI appears to interact with stress-inducednuclear actin rods and might function in theprogression of S-phase (Cameron et al.,

2007). Myosin XVIIIb has been found in asubset of nuclei of primary cardiomyocytesand skeletal muscle (Salamon et al., 2003).

It is a candidate tumor suppressor gene(Ajima et al., 2007), and mutations in thisprotein have been observed in a variety of

cancers (Bleeker et al., 2009). The abovestudies implicate myosins in a number ofnuclear processes. However, none of these

myosins is known to form filaments in thenucleus, and it is unclear how they generateforce in the absence of filaments.

Nuclear myosin I (NMI) was the first

myosin to be discovered in the nucleus(Pestic-Dragovich et al., 2000). It hasbeen studied most extensively and a

complicated picture is emerging withregards to its function in the nucleus. Onthe basis of what we know about actin and

myosin in the cytoplasm, it is reasonable topredict that they interact with each other tofunction as a motor in the nucleus.However, b-actin, the product of one of

the six different actin genes found inmammals (Perrin and Ervasti, 2010) andthe form that is predominantly found in the

nucleus (Hofmann et al., 2004), is necessaryfor the formation of RNA polymerase IIpre-initiation complexes (Hofmann et al.,

2004), but NMI is not. By contrast, NMI isrequired for the formation of the firstphosphodiester bond during transcription

initiation by RNA polymerase II (Hofmannet al., 2006). These results suggest that actinand NMI can work independently (i.e.without working together or hydrolyzing

ATP), perhaps to stabilize proteincomplexes during the early stages oftranscription by RNA polymerase II.

With respect to ribosomal DNA (rDNA)transcription, actin binds to RNA polymeraseI, whereas NMI binds to the transcription

factor TIF1A (Philimonenko et al., 2004). Amutational approach has revealed that NMImotor activity and polymeric actin are

necessary for the efficient transcription of

rDNA (Ye et al., 2008). Chuang and

colleagues also used a mutational approach

to establish that the movement of a

chromosome locus is an active process that

is powered by actin and NMI (Chuang et al.,

2006). This result has been supported by the

demonstration that the activation of genes

located on different chromosomes by

estradiol requires actin and NMI (Hu et al.,

2008), as does the repositioning of a gene

locus (Dundr et al., 2007) and chromosome

repositioning following serum stimulation

(Mehta et al., 2010). Thus, actin and NMI

appear to have a motor function in the

transcription of rDNA and the functional

compartmentalization of the nucleus,

although the molecular details of their motor

activity remain unclear (see Conclusions and

future perspectives).

Nuclear actin and transcriptionActin filaments, which are central to

biological functions, such as muscle

contraction, cell motility, cell division and

vesicle transport, are rarely seen in the

normal interphase nucleus, and phalloidin,

which is commonly used to detect

cytoplasmic actin filaments (Cooper,

1987), rarely stains the nucleus. However,

this does not exclude the presence of

nuclear actin filaments. Sites that are

recognized by phalloidin could be buried

and inaccessible, and/or nuclear actin

filaments could be very short and

extremely dynamic, making them difficult

to detect using currently available fixation

and visualization methods. Another

possibility is that the concentration of

actin in the nucleus is below its critical

concentration for polymerization (0.1–

0.6 mM) (Pollard et al., 2000). However,

this does not appear to be the case because

nuclear actin forms filaments in interphase

nuclei under various pathological

conditions (see below). Thus, cells either

actively limit the formation of actin

filaments in the normal interphase nucleus

or they form short filaments that turn over

very rapidly. Furthermore, the technical

difficulties in detecting nuclear actin

filaments suggest that any type of

filamentous nuclear structure based on

actin will be very different from thin

filaments found in muscle cells and stress

fibers found in the cytoplasm of non-muscle

cells. Because form follows function, for

example in sarcomeres, not knowing the

nature of the nuclear structures formed by

actin is a major conceptual barrier to

understanding of how actin might work inthe nucleus.

Two mechanisms that could regulate the

dynamics and filament structure of nuclearactin are post-translational modifications andthe import-export of actin (reviewed by de

Lanerolle and Serebryannyy, 2011). Althoughcytoplasmic actin is subject to many post-translational modifications (de Lanerolle and

Serebryannyy, 2011), SUMOylation, whichincreases the nuclear retention of actin, is theonly post-translational modification that has

been described for nuclear actin (Hofmannet al., 2009). b-actin shuttles between thecytoplasm and the nucleus, with the importand export of actin being mediated by

importin 9 (Dopie et al., 2012) and exportin6 (Stuven et al., 2003), respectively. Dopieand colleagues also reported that nuclear actin

levels must be maintained to ensure maximaltranscriptional activity, and they suggestedthat there is a close relationship between

nuclear and cytoplasmic actin pools (Dopieet al., 2012). In support of this idea, treatingcells with latrunculin B, a drug thatdisassembles filamentous F-actin in the

cytoplasm, results in the formation ofnuclear actin filaments that are stained withphalloidin (Pendleton et al., 2003). It has been

suggested that the increase in globular G-actinthat follows the depolymerization offilamentous F-actin leads to the translocation

of actin from the cytoplasm to the nucleusand its organization into nuclear structuresthat resemble cytoplasmic actin filaments

(Pendleton et al., 2003).

The balance between G- and F-actin inthe cytoplasm can also affect transcription.The nucleus has to respond to changes in the

external environment, which are frequentlyachieved by turning on and off thetranscription of specific genes. One

mechanism for sending information to thenucleus is through proteins that contain theSUN and KASH domains. Such proteins

contribute to the formation of the so-calledlinker of nucleoskeleton and cytoskeleton(LINC) complexes that physically connectthe nuclear lamina to the actin cytoskeleton,

microtubules and intermediate filaments(Jaalouk and Lammerding, 2009; Simonand Wilson, 2011). Another mechanism

involves regulating the translocation oftranscription factors to the nucleus. Forinstance, the homeobox transcription factor

PREP2 (also known as PKNOX2) (Halleret al., 2004) and the transcriptionalrepressor YY1 (Favot et al., 2005) bind to

actin filaments in the cytoplasm andtranslocate to the nucleus when actin isdepolymerized. By contrast, the transcriptional

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co-activator MAL binds to monomericactin and translocates to the nucleus

upon polymerization of cytoplasmic actin(Vartiainen et al., 2007). Interestingly, theErbB2 growth factor receptor, which isover-expressed in many human tumors,

enhances the transcription of ribosomalgenes by binding to b-actin and RNApolymerase I (Li et al., 2011).

Actin related proteins (Arps) alsoregulate the structure of nuclear actin. Forexample, in the cytoplasm, the Arp2/3

complex nucleates actin filaments andcreates branched actin filaments that areimportant for extending the leading edge ofmotile cells (Magdalena et al., 2003).

Numerous Arps have been described inthe nucleus (reviewed by Oma and Harata,2011). Actin and Arps recruit chromatin

remodeling complexes (Kukalev et al.,2005; Obrdlik et al., 2008; Qi et al., 2011;Blessing et al., 2004), and chromatin

remodeling complexes associate with Arp4and actin (Blessing et al., 2004). Thenucleating activity of Arp2/3 is stimulated

by Wiskott-Aldrich syndrome familyproteins (WASPs), and both Arp2/3 andneural WASP (N-WASP) are found in thenucleus. The polymerization of nuclear

actin by Arp2/3 in a N-WASP-dependentmanner has been implicated in theregulation of RNA polymerase II (Yoo

et al., 2007; Wu et al., 2006). Thissuggests that the ability of Arp2/3 toregulate actin dynamics is conserved in

the nucleus, and that Arp2/3 regulatestranscription in manner that is similar toits effects on actin in the cytoplasm, that is,by regulating its polymerization (Yoo et al.,

2007).

Nuclear actin filaments in pathologyAlthough, as stated above, actin filamentsare not normally detected in interphasenuclei, they can be detected in certain

pathological conditions. Various types ofcell stresses, such as DMSO treatment, heatshock, ATP depletion, treatment withlatrunculin B (as described above) and

viral infections (reviewed by Hofmann,2009) result in the formation of nuclearactin filaments. Expression of the V163M

mutant variant of the a-actin gene, which isonly expressed in muscle (Perrin andErvasti, 2010), also results in the

formation of nuclear actin filaments(Domazetovska et al., 2007). V163M isone of a few naturally occurring mutations

in the a-muscle actin gene that results inintranuclear rod myopathy, a human diseasecharacterized by the presence of nuclear

actin filaments, a decrease in mitotic indexand muscle weakness (Domazetovska et al.,

2007; Vandebrouck et al., 2010). Mutanthuntingtin protein, the causative element inHuntington’s disease, also associates withnuclear actin filaments in response to stress

(Munsie et al., 2011). However, it remainsto be seen whether the nuclear actinfilaments have a function in stress

responses, or whether they contribute tothe pathology associated with any of theseor other diseases.

Interestingly, stressed neurons in cultureform rod-like actin structures that disappearwhen the stress is removed (Bernstein et al.,2006). That study also showed the loss of

mitrochondrial membrane potential andATP following stress is lower in cells withactin rods. As the turnover of actin

filaments is a major source of energyconsumption in neurons (Bernstein andBamburg, 2003), the authors suggest that

the formation of actin rods in the cytoplasmhas a protective effect because it increasesthe amount of ATP that is available forother cellular functions (Bernstein et al.,

2006). By analogy, nuclear actin filamentsor rods should have a similar protectiveeffect. However, these filaments would

have to be readily disassembled when thestress is removed. This does not alwaysappear to be the case. Nuclear

actin filaments in Huntington’s diseaseapparently result from cross-links, formedby a transglutaminase, between actin

and cofilin (Munsie et al., 2011). Howthe formation of relatively stable actinfilaments, such as those found inHuntington’s disease, provides a

developmental or survival advantage to acell is currently unknown.

Actin filaments are also present

following viral infections (Taylor et al.,2011; Goley et al., 2006). Viral particlesare too large (.125 nm in diameter) to

diffuse, and they are usually transportedthrough the cytoplasm on microtubules oractin filaments (Roberts and Baines, 2011).Using cytoplasmic transport as a model, it

has been suggested the movement of viralparticles in the nucleus is an activeprocess. In support of this hypothesis,

viral replication compartments form bymoving and merging with each other in aprocess that requires nuclear actin and

NMI (Chang et al., 2011). Baculovirus(Goley et al., 2006), pseudorabies virusand herpes virus infections also result in

the formation of actin filaments in thenucleus (Taylor et al., 2011; Roberts andBaines, 2011), and the physical association

of nuclear actin filaments with herpes viral

capsids appears to be necessary for thecorrect formation of viral assembly sitesand viral transcription (Feierbach et al.,

2006).

Conclusions and future perspectivesAlthough the presence and functional

significance of actin and multiple myosinsin the nucleus are well established, studieson nuclear actin and myosin paint acomplex picture of how they interact, and

suggest that they behave in fundamentallydifferent ways in the cytoplasm andnucleus. This body of work also raises

many questions with regards to how actinand myosin function in the nucleus at themolecular level.

One of the most enigmatic issues is the

absence of filaments in the nucleus. Thisraises the question of whether actin andany myosin function as a motor complex in

the nucleus. Myosins are defined as actin-activated ATPases. Myosin heads haveATP- and actin-binding sites, and ATP

is hydrolyzed while myosin heads aredetached from actin. When actin andmyosin rebind, myosin uses the energy

that is released from ATP hydrolysis toperform a power stroke that moves actinrelative to myosin. Replacing ADP withATP detaches the myosin from the actin so

that it can repeat the cycle. Myosin II, likemyosin I, is a non-processive motor,meaning that one head can detach before

the other head binds. Myosin II filamentsstay bound to actin filaments because thenumerous myosin II heads bind and

unbind actin non-synchronously. Bycontrast, myosin V is a processive motor,in which one head is always bound toactin. Motor proteins also have to be

anchored to generate tension or performwork. In muscle contraction, ATPhydrolyzed by myosin II is used to move

actin filaments that are anchored to theends of the sarcomere past the myosin IIfilaments. The question, then, is whether

nuclear actin and myosins are bound by thesame kinetic and structural parameters astheir cytoplasmic counterparts.

The best evidence for actin and NMI

functioning as a motor is in rDNAtranscription and chromosome movements(see above). Even though the latter is

supported by multiple studies (Chuanget al., 2006; Hu et al., 2008; Dundr et al.,2007; Mehta et al., 2010), it is difficult to

visualize how actin and NMI can functionas a motor at the molecular level. Thesestudies suggest that chromosomes use NMI

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to move on a type of actin network in thenucleus that has not been visualized to

date. However, NMI, like other class Imyosins, is a single headed, non-

processive motor (Sellers, 2004). It has tobe anchored and a second myosin Imolecule has to bind to actin before the

first myosin I detaches to function as amotor. Otherwise, it would simply float off

the actin filament. One solution to thisdilemma is that NMI belongs to the myosin

IC sub-family, which has a positivelycharged region in the tail domain. It hasbeen proposed that myosin IC moves

cargoes by simultaneously bindingnegatively charged lipids with its tail, and

actin filaments through the actin-bindingsite on its head (Mermall et al., 1998). Wehave previously shown that the NMI tail

binds to DNA and proposed a model inwhich this binding powers the movement

of transcriptional complexes by interactingwith actin that is bound to the polymerase

(de Lanerolle et al., 2005). A crucialelement in this model is that the bindingof NMI to DNA has to be strong enough so

that NMI remains attached to DNA whenNMI hydrolyzes ATP and goes through a

power stroke. This model also demands avery precise spatial arrangement of actin

and NMI relative to each other, thepolymerase and the binding of NMI toDNA. A small misalignment in the binding

of the NMI tail to DNA could make theNMI head unable to bind to actin.

Another possibility is that myosin Vafunctions as a motor to transport viralparticles in the nucleus. Myosin Va

interacts with viral capsid proteins, and anumber of viruses promote the formation of

nuclear actin filaments (Roberts and Baines,2011). Nuclear actin filaments and myosinV appear to have important functions in

viral replication, and it has been proposedthat viruses are moved by myosin V along

nuclear actin filaments that are induced bythe viruses (Roberts and Baines, 2011). This

idea seems feasible because myosin Va is aprocessive motor so that one head alwaysremains attached to the actin (Mermall et al.,

1998), which allows it to walk along actinfilaments. Myosin V has a step size of

37 nm (Yildiz et al., 2003), and actinfilaments form a double-stranded helix

with each node of the helix also repeatingevery 37 nm (Holmes et al., 1990).Consequently, with each ATP molecule

that is hydrolyzed, myosin V can stepfrom one actin to another at the

corresponding location in the next turn ofthe helix (Yildiz et al., 2003). However,

actin filaments must have this precise

registry, and their myosin-binding sites

have to be accessible in order to support

the walking of myosin V molecules. It

remains to be determined if nuclear actin

filaments induced by viruses have this

periodicity.

Thus, many questions remain, although

we have studied actin and myosin for almost

100 years and know a great deal about these

proteins. These studies on cytoplasmic actin

and myosins serve as important models for

actin and its functions in the nucleus.

However, nuclear motors present unusual

conceptual and experimental challenges, and

they might not behave in ways that we

have come to expect on the basis of

their cytoplasmic counterparts. Overcoming

these challenges will undoubtedly result in

exciting new insights into this old family of

proteins.

Funding

This work was supported by a grant from

the NIH [grant number R01GM080587 to

P.deL.]. Deposited in PMC for release after

12 months.

A high-resolution version of the poster is available for

downloading in the online version of this article at

jcs.biologists.org. Individual poster panels are available

as JPEG files at http://jcs.biologists.org/lookup/suppl/

doi:10.1242/jcs.099754/-/DC1.

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