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Desmoplakin Regulates Desmosome Hyperadhesion RP Hobbs and KJ Green Desmoplakin Regulates Hyperadhesion Kallel Sellami M, Zitouni M, Tombari W et al. Peng Z, Rasic N, Liu Y et al. (2002) Mosquito REFERENCES (2007) Anti-desmoglein-1 antibodies are pre- saliva-specific IgE and IgG antibodies in Amagai M (2010) Autoimmune and infections skin valent in Tunisian patients with hydatidosis 1059 blood donors. J Allergy Clin Immunol diseases that target desmogleins. Proc Jpn and leishmaniasis. Br J Dermatol 156:591–3 110:816–7 Acad Ser B Phys Biol Sci 86:524–37 Kamhawi S (2000) The biological and immuno- Remoue F, Alix E, Cornelie S et al. (2007) IgE Aoki V, Millikan RC, Rivitti EA et al. (2004) modulatory properties of sand fly saliva and and IgG4 antibody responses to Aedes Environmental risk factors in endemic pem- its role in the establishment of Leishmania saliva in African children. Acta Trop 104: phigus foliaceus (fogo selvagem). J Investig infections. 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Int Arch Allergy Immunol ization of a protective salivary protein. J Exp Exp Immunol 137:195–200 114:367–72 Med 194:331–42 Desmoplakin Regulates Desmosome Hyperadhesion Journal of Investigative Dermatology (2012) 132, 482–485; doi:10.1038/jid.2011.318; published online 13 October 2011 TO THE EDITOR Desmosome assembly is a calcium- intercellular adhesive strength termed The skin is subjected to continuous dependent process, where major cyto- hyperadhesion (Cirillo et al., 2010; physical stress. Keratinocytes resist plasmic plaque components of the Thomason et al., 2010). It has been mechanical stress by tethering the desmosome (e.g., DP, keratin) coalesce hypothesized that the acquisition of tension-bearing keratin intermediate with other desmosomal proteins (i.e., hyperadhesion is essential for the epi- filament cytoskeleton to sites of inter- cadherins, armadillo proteins) at sites dermis to resist the perpetual mechan- cellular contact known as desmo- of nascent junction formation (Pasdar ical stress to which it is subjected somes (Green and Simpson, 2007; et al., 1991). Desmosomal proteins (Garrod and Kimura, 2008). Garrod and Chidgey, 2008). The accumulate at cell–cell borders over The underlying signaling and struc- plakin protein desmoplakin (DP) is time to form robust intercellular junc- tural properties that govern desmosome an obligate desmosomal constituent tions capable of resisting mechanical maturation and acquisition of hyperad- necessary for keratin anchorage at stress. More recently, it has been hesion have only recently begun to be cell–cell contacts. Establishing and reported that as desmosomes mature studied in greater detail. The data maintaining the DP–keratin association over the course of several days, they no suggest that activation of protein kinase is essential for regulating desmosomal longer require calcium to maintain C (PKC) in hyperadhesive epithelial adhesive strength in both developing intercellular adhesion (Wallis et al., sheets of Madin-Darby canine kidney epidermis and adult stratified tissue 2000; Cirillo et al., 2010). Calcium- or HaCaT cells is sufficient to convert (Vasioukhin et al., 2001; Huen et al., independent desmosomes have been desmosomes from calcium-indepen- 2002). associated with a state of enhanced dent to calcium-dependent (Wallis et al., 2000; Cirillo et al., 2010). Like- Abbreviations: DP, desmoplakin; Gly, glycine; PKC, protein kinase C; Ser, serine wise, inhibition of PKC signaling is 482 Journal of Investigative Dermatology (2012), Volume 132 RP Hobbs and KJ Green Desmoplakin Regulates Hyperadhesion DMSO PMA 2 Days 6 Days 2 Days 6 Days Wild-type DP expressing 2 Days 6 Days 2 Days 6 Days DP S2849G expressing 100 Wild-type DP * 90 DP Ser2849Gly Wild-type DP DP S2849G expressing expressing 80 70 * 60 siDP ––+ + ––+ + * Dox ––++ ––++ 50 40 No. of fragments No. 30 ** 20 IB: DP (NW6) 10 0 Day 2Day 6Day 2Day 6 DMSO PMA Figure 1. DP Ser2849Gly promotes hyperadhesion. (a, left) DMSO-treated A431 epithelial sheets resist mechanical stress following 6 days at confluency, but not at 2 days. (a, right) Protein kinase C (PKC) stimulation is sufficient to weaken the adhesive strength of day 2 and day 6 sheets. (b, left) A431 sheets expressing desmoplakin (DP) Ser2849Gly exhibit enhanced stress resistance at day 2, and (b, right) do not respond to phorbol 12-myristate 13-acetate (PMA)-induced fragmentation. (c) Western blot of A431 monolayers collected in urea sample buffer at day 6 and probed for DP (NW6) showing doxycycline (Dox)-induced expression of exogenous DP in the absence of endogenous DP (siDP lanes). (d) Quantification of fragments under each condition in a and b. Graph represents three independent experiments, performed in triplicate. Bars ¼ mean±SEM. *Po0.01 (Bonferroni-corrected two-factor analysis of variance (ANOVA) with replication, a ¼ 0.0125) for the interaction between the indicated groups of data. **Po0.02 (Bonferroni-corrected single-factor ANOVA, a ¼ 0.0125) between the indicated data sets. IB, immunoblot. adequate to promote calcium-indepen- hyperadhesive cells may undergo a DP–keratin anchorage is critical for dence and hyperadhesion acquisition structural reorganization on wounding maintaining intercellular adhesive (Wallis et al., 2000). Additionally, (Garrod et al., 2005). Altogether, these strength in epithelial sheets (Huen hyperadhesive epithelial sheets become findings suggest an ‘‘inside-out’’ signal, et al., 2002). Thus, we hypothesized calcium-dependent on wounding, and whereby PKC-driven modification of that regulation of the DP–keratin asso- PKCa has been reported to localize to a desmosomal component may induce ciation might contribute to the desmo- the desmosome at the leading edge of a structural rearrangement within some maturation process necessary wounded epithelial cell sheets (Wallis the desmosome to facilitate the loss for establishing calcium-independence et al., 2000; Garrod et al., 2005). of hyperadhesion and the formation and robust resistance to mechanical Furthermore, a transmission electron of calcium-dependent desmosomes. stress. To test our prediction that microscopy and crystallographic mod- However, the events downstream of enhancing the DP–keratin interaction eling study reported that the ectodo- PKC signaling have yet to be eluci- would promote the acquisition of hyper- mains of desmosomal cadherins in dated. adhesion in epithelial sheets, we took www.jidonline.org 483 RP Hobbs and KJ Green Desmoplakin Regulates Hyperadhesion Maturation SCC12f cells constitutively expressing Assembled desmosome wild-type DP or mutant DP (Supple- mentary Figure S1b online). Impor- Assembly tantly, these results were obtained in PKCα Intercellular PKC stimulation the background of endogenous DP activity adhesive strength depletion using small interfering RNA oligos targeting the DSP 30 untranslated region, which ensured that the induci- Modulation of desmoplakin–keratin
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