Journal of Cell Science pteilBooyGop nttt fMdclBiology, Medical of Institute Group, Biology Epithelial Birgitte E. Lane* and Haines L. Rebecca glance a at disease and astv ahgncmttosi the of in identification The pathogenic drugs. causative many dismantled completely and by which rapidly be systems, can and to contrast in disrupted, easily inert are not that very networks as nanofilament filament form of they thought because be or to used , filament III–VI) (types related intermediate highly other and epithelial II), and other I (type Keratins and 1). (Table skin tissues (sheet) in found filament-formingproteins cytoskeletal are Keratins 10.1242/jcs.099655 doi: 3923–3928 ß 125, Science Cell of Journal ( correspondence for *Author Singapore Immunos, 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. 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Table onc egbuigcls n through and cells, which neighbouring into 1994), connect al., et (Kouklis perimeter. through desmosomes cell link the anchor Keratins around and form cell junctions keratin the into in of bundles ropes branching cytoplasmic The keratins of behaviour Dynamic McLean, 2007). and severe al., et most (Lane Uitto 2004; the mutations for motifs, disease hotspots termination are and which initiation conserved highly the helix are domain rod the of h ao eaissnhssdi aa cells basal in are synthesised keratins K14 major For and the K5 stress. during epidermis, to the in response profile example, in or expression to differentiation keratin cells alter they epithelial their while network allow intact an to maintain is needed filaments of also disassembly and Dynamic assembly healing. wound during to migrate and flexible growth to during proliferate and to epithelium. plastic cells allow dynamic, be the must cytoskeleton filament three keratin the through in However, cells anchors dimensions network filament– junction This substrates. to attachment cells their connect which (Andrahemidesmosomes, taiideihla ar adstructures hard hair, epithelia: Stratified suprabasal ta. 03 into 2003) al., et ¨ n oe fflmn sebyhsbeen has assembly filament periphery, Turnover of cell model this. a the and at on 2010) accelerated light be al., might shed New et soon Schermelleh could microscopy. techniques limit by (reviewed light resolution microscopy the super-resolution standard below size of its is as confirmed nm) been (60 not precursor, has this nucleation but the (see be filament length might unit (Liovic poster) The cytoplasm 2003). al., that the et particles the throughout subfilamentous throughout occur tiny synthesised do; as be cell microtubules can as they centres defined organizing have not do filaments Intermediate the differentiation. of during network of filament integrity the re-assembly structural complete A the preserves 2011). than network, and al., rather et disassembly transition, Windoffer 2009; gradual Eriksson in al., 1993; al., persist et et (Kartasova K1 can K10 alongside al., K14 and poster) (see et and cells (Denk K5 suprabasal keratins and simple 1987), for days 4 around half-life, long a have proteins keratin However, differentiation). into ‘locked’ and are (which K1 cells suprabasal in expressed whereas are K10 proliferate), can (which hr okrtn sebei h cell? the in assemble keratins do Where K6a Journal of Cell Science ta. 2011). before the cell al., et into (Windoffer adhesions, the integrating network peripheral pre-existing then focal in and that elongating at nucleated proposes periphery are that filaments described recently uainrdcsteaiiyof mechanical the ability on mutations 2001). of under impact al., The et bundle (Ma the this conditions to cross-linking vitro, filaments reduces In reconstituted 1991). al., mutation (Ishida- et of aggregates hotspot Yamamoto formation keratin the the K14 cytoplasmic in as Dowling–Meara severe result p.Arg125Pro, such cause the EBS, that of For mutations some disease. less-stable cause a example, and yield network to 2004) filament al., 2002; et al., Owens et (Herrmann filament kinetics their assembly or altering junctions into by integration ways, their modifications, many post-translational their in function interrupt can cell keratins in change acid al., amino et 2009). (Flitney al., et stress in Sivaramakrishnan shear remodelling 2009; filament to K18 keratin response and K8 C of for kinase protein barrier by on Phosphorylation filaments defined fewer Omary but keratins. by 2006) (reviewed al., et keratins known simple sites on many with phosphorylation, is modification the well-documented situations. most modulate specific The in to keratins al., likely of et solubility are Snider and which 2010; al., al., 2011), et et Ku sumoylation Srikanth 2006; 2010; al., et described (Omary phosphorylation ubiquitylation, acetylation including been to keratins, have on modifications the cell (Wo the prevents periphery in as precursors kinases filament of these formation also kinases, p38 of the might inhibition protein by adhesions 2006) phosphorylation mitogen-activated al., on focal depend et at (Windoffer assembly actin- (Ko Keratin periphery the cell in in plectin the keratins of implicated and movement al., inward been 2009), dependent et also al., filament (Spurny has et Kostan fibroblasts) intermediate 2008; in (the protein of influence dynamics filaments to and known formation the is cell Plectin different at locations. filaments intermediate actin protein bind or linker isoforms plectin the because plectin is keratins assembling ierneo post-translational of range wide A the localising for cofactor probable A osdrn l h bv,ee single a even above, the all Considering l ta. 2007). al., et ¨ll lc ta. 2009). al., et ¨lsch f srequired is eiineo pteiltsusi discussed is below. tissues epithelial of resilience ieyta uain le h yaisof dynamics the alter mutations appears that a It likely 2004). survive al., et (Russell to mutant keratins wild- type able expressing those expressing than less stretch repetitive much 2012). cells are al., keratins et the Beriault 2008; However, can without al., filaments et wild-type (Fudge 100%) as much expressing as death cells than cell uni-directional or damage p.Arg125Pro significant (greater withstand the stretch can GFP- carrying a mutation K14 expressing line tagged cell A formation. keratinocyte filament preventing by resilience simply mechanical in reduce not mutations do that keratins suggest studies 2011). However, Moore, and (McLean tissues to of and stability cells role mechanical providing crucial in the keratins reflects diseases keratin shear 2009). al., to et subjected (Flitney to stress are 2007). appears cells Fudge, filaments when increase keratin and of Kreplak Bundling 1991; al., (Janmey hardening et strain show they strains,where high at microtubules than and brittle strains, less low at filaments less actin being than keratin rigid tough, and that flexible are show filaments properties surrounding mechanical the into single-filament source of Investigations epithelium. a generates from away stress mechanical as dissipate will tissue, network the the network across resilience mechanical conferring hemidesmosome keratin– By and keratin–desmosome epithelial the 2012). an sheet, across al., continuity epidermis mechanical the et as (Beriault such epithelia in stratified particularly forces, mechanical withstandsignificant can network filament keratin The resilience mechanical with epithelia provide Keratins euti isefaiiydet euto in reduction a to due fragility tissue in al., result might disease mutations et keratin alternative which Wagner in an mechanism 2009; al., suggests This al., et 2012). et (Long Liovic proteins 2006; linker and a components cytoskeletal desmosome or of reduces mutations, expression also expression, keratin keratin in of reduction 2003). more presence al., et filaments The (Morley keratin migration for its quickly cell re-organise the allowing to dynamic, more is the in network because faster perhaps counterparts, migrate their wild-type than K14 assays with wound scratch or culture patients tissue K5 EBS in mutations from generated keratin lines a to rise networkthatislessstable.Furthermore,cell giving formation, filament h isefaiiyosre nmany in observed fragility tissue The ora fCl cec 2 1)3925 (17) 125 Science Cell of Journal nrsos osrs,sgetn an the in al., suggesting et proteins Toivola by these (reviewed stress, response stress for to role important response upregulated in is keratins many of response Expression stress alter keratins Mutant sections. in following discussed the are 2009; These al., 2010). al., et et Toivola Omary 2007; (Gu Coulombe, differentiation and tissue and positioning organelle responses, for stress has essential non-mechanical including mice, processes, are cellular different keratins many transgenic that and suggested knockout as inligi epnet xenlstresses SAPK external to accelerated response to in and signalling cell amplified a K14 or of show K5 mutated response expressing the Cells stress. alter also EBS thus and Ku activity, 2006). poster; Omary, (see (SAPK) apoptosis preventing kinase stress-activated protein phosphorylated which absorbs hyperphosphorylation, sponge’, ‘phosphate undergoing been a as has acts It K8 2009). of suggested al., et situations (Omary constitute stress predispose cell toxins which by viruses, still mediated or injury in why liver but to silent carriers explain are individuals, keratins al., help most these et might in Omary mutations 2007; such This al., to 2009). et tolerance (Ku the assaults mechanically by reduce keratin liver, damage in mutations less and, to alcohol, as vulnerable such By toxins is is 2004). but stressed liver Lane, tissue and initiate contrast, (Owens by might damage caused mutations the digestion) keratin in during peristaltic resilience withstand movement 2003). to al., mechanical (required et intestine of (Ku with disease Loss patients liver or some al., et 2004) for (Owens disease bowel factors inflammatory identified risk been have as K18 2001; and K8 al., keratins et 2004). (Freedberg Coulombe, and stress is DePianto oxidative UV K17 and healing, or in and wound or to K16 cytokines, of response inflammatory expression K6b, by induced the K6a, particular, keratins In 2010). ela aafo xeietlmdl such as models experimental fragility, from tissue data as with well associated not that are diseases keratin human from Evidence keratins functions for multiple are there that suggest phenotypes disease Keratin decreased to tissue. the leading of stability proteins, junction uain nK n 1 htcause that K14 and K5 in Mutations epithelial simple the in Mutations Journal of Cell Science hrceie yardcino insulin- of reduction a by characterised 1i pancreatic in expressing K1 mice example, in For alteration 2003). is Lane, subsequent and Owens that in a (discussed properties fate physical and to profile cell lead keratin might in altered the change in reflected a be to might related these can cell effects; a wide-ranging markers in have expressed Changing are prognostic that 2011). keratins the Karantza, as by and (reviewed 1990), recently Alexander, more and of in have tissue (Lane the expression origin identify to keratin tumours epithelial tightly Histopathologists used therefore historically and is development controlled. in and early differentiation of set is pattern keratins expression tissue-specific The expression by keratin affected is differentiation Tissue al., 2007). et (Planko is uncoating which vesicle HSC70, in fullyinvolved chaperone the with interaction K5 not an of involve might is it understood, arrangement alter melanosome keratins epidermal by in of mechanism mutations which skin the in transfer in Although changes arrangement pigmentation. to the lead their can in keratinocytes, the or defect over cap melanosomes, distal A a nucleus. in arranged where are keratinocytes they basal into and transferred melanocytes by produced are (pigment-containinggranules) al., Melanosomes et (Uttam Lugassy 2006; 2006). al., present) et Betz (when 1996; al., linked et blistering directly not skin hypo-pigmented is to phenotype that and poster) pigment see hyper- skin skin; of a Dowling–Degos keratin(patches have K5 K14 rare in mutations or by of caused including are group that disease, A 2008). diseases, al., Kumemura et 2005; al., et Toivola 2004; (Kumemura al., et poster) (see membrane events certain trafficking in proteins these a for revealed role have keratins some in Mutations transport organelle 2010). and Keratins al., network et Lo Rogel 2010; 2008; al., keratin et or al., Na 2010; the mutated et integrate of (Jaitovich into cannot presence that efficiently keratins the misfolded stress by during increased al., and filaments is keratin et degradation of for (Russell targeting The apoptosis increased 2010). their to to resistance contributes the cells these and in signalling (ERK) extracellular- 2002), kinase signal-regulated of al., upregulation constitutive et (D’Alessandro 3926 ora fCl cec 2 (17) 125 Science Cell of Journal b el eeo diabetes develop cells fe tal., et ¨ffek eeino 1 namuemdllasto leads model mouse 1993). a in al., K17 of et Deletion (Blessing vesicles secretory ta. 07 seposter). Schweizer (see 2007) 2005; al., al., et hair-follicle- et mucous (McLean in palmoplantar fragility surfaces either cell or cysts painful associated and by characterised dystrophy, , disorder nail pachyonychia a or congenita, to , fragility lead hair syndrome the appendages including defects these of various in the keratins the expressed in and maintenance in Mutations follicles glands). important sebaceous (hair appendages and also epidermal expression is development correct keratins The of normal function. for crucial tissue is keratins correct the expression of and that Paladini indicating 1998; 1999), Coulombe, al., to et leads differing (Hutton which to only degrees phenotype, in the K18 in of or rescue K14, partial reflected K16 of of is and knockout expression keratin Lee mouse This II 2002; the 2009). type al., or Coulombe, et by I (Yamada altered type present drastically the the be changing that can the of filaments suggest properties mechanical K14, and its assembly than rather partner, K18 or normal differentiation. K16 with paired as tissue such K5 pairs, keratin on ‘unnatural’ of Studies effect it more phenotypes, a general has these K17 of of deletion could that some likely seems K17 to of rise loss give which by 1- potential mechanisms suggest type domain) receptor death associated factor the necrosis 14-3-3 with (tumour protein K17 of adaptor interactions Tong 2006; Although 2010). al., al., et DePianto 2006; inflammatory et Coulombe, and (Kim altered profile an cytokine protein and and size synthesis), cell in repair decrease wound a (through cycling, follicle hair in defects n ihu ob ute siRNA-based further doubt a first 2010), without al., the and et in (Leachman of route feasibility therapeutic K6a recently the patient demonstrated mutant congenita pachyonychia RNA against interfering small (siRNA) of trial A successful way. some mutant in network keratin the the stabilise to of therapies small-molecule different (ii) ablation and protein, two genetic (i) on keratin areas, focussed to have approaches diseases therapeutic far, So therapy for Opportunities the for therapies of diseases. keratin development crucial the be will described to defects the give to mutations rise how and processes, these in nesadn h rcs oeo keratins of role precise the Understanding s n TRADD and yposb euigteaon of amount the the ameliorate to reducing keratin possible by severe be symptoms In might observed, are 2011). it aggregates where al., disorders, To et 2007; al., Zhao et promoter (Kerns the K6a moderately for of which activity the of statins, downregulate expression include keratin. specific the They a target alter or keratins either several they and expression, keratin modulate to now shown have been molecules small Several cell. in being the levels keratin also manipulate to are investigated therapies keratin Nevertheless, small-molecule caution. alter must with approached purposes to be therapeutic for attempts expression differentiation above), have tissue can (see on expression effects As keratin dramatic 2010). in Linsley, of However, changes and effects (Jackson 2011). off-target siRNA expressed potential al., been regarding have et concerns al., significant et Liao (Atkinson 2011; follow will approaches rvd seta nomto nti area, this understood. in information might yet essential mutations provide the not keratin are but dynamics Disease-causing controlled keratin the likely, which are within more by exchange mechanisms seems subunit network for some of and observed 2011)] form al., been et (Helfand re- has vimentin filament [as dynamic organisation highly combination localised A of junctions. tissue, cell are intact at and stable anchored an be to appear in dynamic, filaments where cells highly with the is compared where cell, cytoskeleton dividing keratin or migrating a different However, be in to above. likely are presented and dynamics filament was of elongate centre cell, the and towards the move periphery they as cell filament mature the of nucleated model in are filaments One which in cell. dynamics, the dynamics within and poorly assembly the filament is are of as control domains, 2003), al., tail et (Strelkov and understood of head role the substructure the of particular the in and of filaments, significant keratin details the Despite effort, transport. and differentiation cell organelle tissue the this response, in involved to with stress are keratins Associated resilience function, tissues. mechanical epithelial function providing crucial a in have filaments Keratin Perspectives 2011). to al., (Lo et cytoskeleton Chamcheu correctly filament chemical way’ keratin reform the of the ‘clear for use could which the chaperones, with aggregation fe ta. 2010; al., et ¨ffek ¨rma ,2011; ¨, Journal of Cell Science . alus,A n To and A. Liovic, I., Vahlquist, Pihl-Lundin, H., M., Navsaria, C., J. abnormalities. Chamcheu, two keratin Jr 1202-1205. in H., for evidence E. simplex: Epstein, families and bullosa L. Epidermolysis A. (1991). Rothman, M., cytoskeletal J. with Bonifas, production. interferes insulin mice and transgenic order pancreatic of in cells islet epidermal of synthesis Ectopic Ru to M., lead gene Blessing, 5 keratin disease. the Dowling-Degos in mutations Loss-of-function odto.Udrtnigteconnection the keratin physiological Understanding the of condition. reflect better models to to diseases laboratory to order necessary be In improve will it tissues. issues, these epithelial address fragile rise give to changing dynamics and how formation filament explaining in particularly eaioye rmha tesidcdkeratin and stress-induced proteins shock simplex heat heat kinases. of MAP bullosa involvement from aggregation: epidermolysis keratinocytes protect chaperones Ru M., Braun-Falco, J., S., Hanneken, Bu Wenzel, S., M., Eigelshoven, S. L., Pasternack, Planko, C., R. Betz, keratin keratinocytes. 7 NEB-1 K14-R125P S. in D. mutant networks Fudge, and of in bundles and behavior B. E. mechanical Lane, mutations The Robinson, D., V., Russell, J. J., McCuaig, 5 Z. O., Haddad, R., D. keratin Beriault, H., for 2079-2086. and Liao, simplex. T. bullosa B. E., siRNA epidermolysis C. of Moore, V. D., therapeutic I. J. H. McGilligan, W. F. McLean, Smith, D., I., rescue Szeverenyi, S. Atkinson, G. keratinocytes. (-/-) Dermatol. Wiche, Plectin-isoform-specific Invest. plectin and in I. defects hemidesmosomal Fischer, P., (2003). Fuchs, D., Spazierer, Andra References doi:10.1242/jcs.099655/-/DC1 http://jcs.biologists.org/lookup/suppl/ at files JPEG available as are at panels article poster this Individual of jcs.biologists.org. version for online available the is in poster and downloading the of version high-resolution Technology A Council, Science, Singapore. Research (A*STAR), Research for Biomedical Agency the supported is by laboratory authors’ the in in Work (IMB assistance Funding Wright for the Graham images. Unit) producing Declan of and Common, John Microscopy reading John thank Lunny critical and to like manuscript, for would Common authors The Acknowledgements diseases. therapeutic keratin new for yield interventions this hopefully a in will is investigations area diseases further and keratin priority, certain are in that the observed phenotypes in and unrelated filaments resilience apparently keratin mechanical of providing role the between e31320. , ,K,Krakr . Jo I., Kornacker, K., ¨, .Ivs.Dermatol. Invest. J. te,U n rne .W. W. Franke, and U. ¨ther, 120 21) eeomn fallele-specific of Development (2011). 189-197. , so,H,VnDnBget K., Bogaert, Den Van H., ¨ssow, m .Hm Genet. Hum. J. Am. ¨rma .Cl Biol. Cell J. .Ivs.Dermatol. Invest. J. ,H. ¨, rl . Zo A., ¨rgl, te,A tal. et A. ¨tten, 131 1684-1691. , 21) Chemical (2011). 120 Science 78 743-755. , LSONE PLoS rr M., ¨rer, 510-519. , (1993). (2006). (2012). 254 131 J. , , iaet nmcaial tmltdA4 cells. A549 Chem. stimulated A., mechanically M. Ciechanover, in intermediate filaments K. keratin N., of Ridge, degradation Na, and target proteasome-mediated D. S., R. for Mehta, Goldman, A., effects application. Jaitovich, off-target therapeutic Discov. Drug and siRNA S. identification avoiding P. Linsley, and and L. A. keratin- Jackson, abnormal A. K14. and an Dermatol. R. K5 keratins by involving Eady, network characterized filament and a disease B. is type) genetic E. (Dowling-Meara simplex Lane, bullosa Epidermolysis M., J., I. simple S. Chapman, M., Leigh, A., and J. Yen, McGrath, stratified A., Ishida-Yamamoto, C., E. of Q. Fuchs, keratins epithelia. Yu, and between D., A. differences R. P. Paladini, Coulombe, E., Hutton, keratins. human B. Biol. recombinant E. of Lane, M., intermediates R. U. Porter, Aebi, T., and Wedig, H., Herrmann, eino . en,M . lgs,A .and A. immune A. the skin. polarizing in by Dlugosz, response growth tumor L., and proliferation M. A. P. Kerns, Coulombe, D., DePianto, repair. tissue A. and P. filaments Coulombe, and D. DePianto, ur pn elBiol. cytodynamics. Cell structural and Opin. Curr. multi-talented cytoarchitecture U. associates: specifying Aebi, elements their and and filaments H. Herrmann, ek . akne,E,Ztokl .adFranke, and hepatocytes. K. mouse Zatloukal, W. E., W. Lackinger, H., stress Denk, of shock. kinetics osmotic the B. to response alter E. simplex Davies, Lane, bullosa M., epidermolysis and S. M. Morley, D., A. Russell, M., D’Alessandro, 1311. ietnognzto ouae h omto of al. et formation M. the K. Hahn, modulates P., I., lamellipodia. N. organization U., Y. S. Aebi, Wu, S., Vimentin Murthy, Mahammad, T., G., B., Grin, Wedig, M. K., Mendez, D. Shumaker, T., and B. mutagenesis Helfand, site-specific of 1210. use expression. keratins: protein type recombinant II of heterodimer and a is I filaments keratin surprising assembled vitro K. with Weber, and palette M. Hatzfeld, broadening a shades. epithelia: skin A. P. in Coulombe, and L.-H. of Gu, unit structurally filaments. protofilament K. nm the three 10 Weber, along of domains and distinct characterization E. Kaufmann, Proteinchemical N., remarkably is Geisler, keratinocytes resilient. and human extensible cultured Lane, in W. W., A. network Moore, Vogl, D., and B. Beriault, E. D., Russell, D., Fudge, ains eei n ucinlanalyses. functional simplex and bullosa epidermolysis genetic of patients: E. genes A., 14 Fuchs, Hebert, keratin and A., human S. Letai, E., A. M. Paller, Hutton, A., P. Coulombe, rebr,I . oi-ai,M,Kmn,M and cycle. M. activation Komine, M., M. intermediate Tomic-Canic, Blumenberg, keratin M., I. of Freedberg, remodeling on stress and filaments. shear of assembly and effects A. the the cells: S. epithelial Adam, of properties D. R., E. R. Kuczmarski, Goldman, W., E. Flitney, ihohrflmnosbooye networks. 113 biopolymer Schliwa, filamentous other and with P. Traub, U., M. Euteneuer, A., P. 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