Desmosomes

keratinocyte adhesion, bullous disorder

1. Jai Kumar Pillai KIMS, Bangalore 1 DESMOSOMES

2. EPIDERMAL ADHESION Epidermal integrity is required for protection against mechanical , physical & microbial insults The major cellular structures involved in maintaining this cell-cell adhesion are the desmosomes 2

3. Other epidermal attachment complexes Adherens junction Tight junction Gap junction 3

4. DESMOSOMES Macula Adherens Intercellular bridges Major cell adhesion jn of epidermis Anchor apposing keratinocyte cell membranes to intracellular KIF Location – all epithelial tissues , myocardium & cortex of LN 4

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6. C/S: symmetric, consists of 2 apposing dense plaques inside membranes Intercellular centre- Desmoglea , 30nm Thin electron dense midline in centre(formed by amino terminus of desmosomal cadherins ) Inner dense plaque & outer dense plaque 6 ULTRASTRUCTURE

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8. Biochemical Characterisation 3 Major Gene Families Plakins ( desmoplakin ) Armadillo proteins( plakoglobins & plakophilins ) Desmosomal cadherins ( desmogleins & desmocollins ) Additional proteins- perp , ninein , kazrin & corneodesmosin 8

9. Outer dense plaque 10-20nm from plasma membrane Contains desmosomal cadherins cytoplasmic tails, plakoglobin , plakophilin , amino terminus of desmoplakin Inner dense plaque 40-50nm from PM Carboxy terminus of desmoplakin interacting with KIF 9

10. DESMOPLAKIN Major inner plaque component Exists as 1 & 2 Family includes BPAG1, Plectin plaque proteins of HD envoplakin & periplakin 10

11. Modular protein Rod like centre C terminus binds to KF , Amino terminus binds to plakoglobin Major link b/w KIF & desmosomal plaque Also play role in development of epithelium 11

12. APPLIED ASPECT Mutations causes PPK(striate or diffuse) Dilated cardiomyopathy Wooly hair Skin blisters Haploinsufficiency AD striate PPK 12

13. Non-sense mutation affecting desmoplakin1 Naxos like syndrome- PPK, Wooly hair & ARVC Compound heterozygous mutation Lethal acantholytic epidermolysis bullosa widespread epidermolysis generalized alopecia anonychia neonatal teeth Total skin denudement Absent toe nails Total alopecia Single row of BK 13

14. PLAKOGLOBIN γ - catenin 2 nd major protein in desmosomal plaques Ubiquitously present in all epithelia Can also localise to nucleus & modulate gene transcription Link between desmogleins & desmocollin to desmoplakins 14

15. APPLIED ASPECT Plakoglobin mutation result in NAXOS disease Diffuse PPK Wooly hair ARVC 15

16. PLAKOPHILIN Binds to desmoplakin & desmosomal cadherins Aids in clustering & stability of plaque Localise to nucleus where it regulates translation & cell proliferation 16

17. APPLIED ASPECT Plakophilin1- mutation causes Ectodermal dysplasia skin fragility syndrome Sparse hair, skin erosions Perioral erosions Intraepidermal clefting 17

18. Plakophilin2- mutation are mcc of AD arrythmogenic RV cardiomyopathy 18

19. DESMOSOMAL CADHERINS link between the intracellular plaque & the extracellular desmoglea Ca2+ dependent adhesion Desmogleins-4 isoforms (1,2,3,4) Desmocollins 3 isoforms-1,2,3 Key role in initiating desmosomal assembly 19

20. Desmoglein 1 & 3 – predominant in epidermis & mucous membranes, thymic epithelial cells Dsg2- major isoform in most simple & transitional epithelia , cardiac myocytes Dsg4- more in hair follicle, testes & prostate Dsg3- expressed in SCC, molecular target for therapy 20

21. DESMOCOLLINS 3 isoforms-1,2,3 Dsc 3- expressed in stratified squamous epithelia of skin & oropharynx Dsc2-only isoform present in cardiac tissue 21

22. Mechanism of intercellular adhesion Amino terminal tryptophan of 1 cadherin molecule Interacts with a hydrophobic acceptor of another cadherin molecule in adjacent cells Forms trans-adhesive interphase Interactions are homophilic ( Dsg-Dsg ) & heterophilic ( Dsg-Dsc ) 22

23. Applied Aspects Dsg1-target of proteolytic cleavage in Bullous Impetigo SSSS Inherited Icthyosis a/w Netherton syndrome 23

24. SSSS- cleavage of Dsg1 by staphylococcal exfoliative toxin , occurs between extracellular domains 3&4 Extensive areas of desquamation Perioral crusting, fissuring 24

25. Pathogenic antibodies to Dsg1 Pemphigus foliaceus MC pemphigus vulgaris Paraneoplastic pemphigus 25

26. AD mutations causing Haploinsufficiency of Dsg1--- Palmoplantar Keratoderma 26

27. DESMOGLEIN 2 & DESMOCOLLIN 2 Implicated in CVD as a cause of AD arrythmogenic RV cardiomyopathy 27

28. DESMOGLEIN 3 Target of autoabs in Mucosal & MC pemphigus vulgaris Paraneoplastic pemphigus Target-Amino terminal extracellular domains of Dsg3 28

29. DESMOGLEIN 4 & DESMOCOLLIN 3 Mutations lead to AR forms of hypotrichosis & monilethrix Beaded appearance of hair 29

30. DESMOCOLLIN 1 Target of autoAbs in Subcorneal Pustular Dermatosis of IgA Pemphigus Flacid pustules, erythematous skin Circinate pattern Neutrophil infiltrate 30

31. Desmoglein Compensation Theory 31 Dsg3 compensates for Dsg1 Dsg3>Dsg1 Dsg1 compensates for Dsg3 Low Dsg1

32. OTHER DESMOSOMAL PROTEINS Envoplakin & Periplakin Expressed in superficial layer of epidermis Incorporate into corneodesmosomes of SC Paraneoplastic pemphigus : Autoantibodies to these proteins are characteristic 32

33. Corneodesmosin Secreted gp Incorporates into corneodesmosomes Expressed in inner root sheath of hair follicle Mutation AD hypotrichosis simplex of scalp Scalp biopsy- loss of cohesion in inner root sheath & aggregates of corneodesmosin around hair follicle 33

34. FUNCTIONS Major- cell adhesion Development & differentiation of epidermis May mediate signal transduction( armadillo family B- catenin , plakophilins ) B- catenin — wnt signaling pathway Translocates to nucleus to form a transcription factor 34

35. ADHERENS JUNCTION Electron dense , transmembrane structures, engage with actin skeleton Functions epithelial assembly, barrier formation cell motility, changes in cell shape 35

36. U/S: characterised by 2 opposing membranes Seperated by gap of 20nm & 0.2-0.5um in diam Comprises of 2 basic adhesive units nectin–afadin complex and the classical cadherin complex 36

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38. Cadherins form a complex with the catenins (α-, β-, and p120 catenin ) & help mediate adhesion and signalling Nectins form a structural link to the actin cytoskeleton via afadin (AF-6) 38

39. Applied Aspects P- cadherin (CDH3) mutations result in AR hypotrichosis with juvenile macular dystrophy 39

40. TIGHT JUNCTIONS Zonula occludens Major regulators of permeability in epithelia Skin barrier integrity & maintaining cell polarity Function: regulate the paracellular flux of water-soluble molecules between adjacent cells 40

41. Structural components- Claudin (24 subtypes)—main is 1&4 IgG -like family of junctional adhesion molecules (JAMs ) Occludin claudins and occludins can bind to the intracellular zonula occudens proteins ZO-1, ZO-2, ZO-3 Can interact with actin-direct link with cytoskeleton 41

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43. Tight jn , adherens jn & desmosomes form the apical junctional complex in ep cells 43

44. Applied Aspects C laudin 1 –AR diffuse ichthyosis with large scales, hypotrichosis , scarring alopecia & sclerosing cholangitis claudin 16(paracellin-1)-familial hypomagnesaemia with hypercalciuria and nephrocalcinosis claudin 14 - AR deafness disorder ZO-2 - familial hypercholanaemia 44

45. GAP JUNCTIONS Comprise clusters of intercellular channels, known as connexons 1 connexon formed by assembly of 6 connexin subunits within Golgi At PM, adjacent connexons associate to from Gap junction Stability of Gap jn regulated by PKC, Src kinase , Ca2+, calmodulin and pH 45

46. Connexins (α, β and γ) – forms homotypic or heterotypic connnexons 46

47. Functions Sharing low-molecular-mass metabolites (< 1000 Da ) & ion exchange between neighbouring cells cell synchronization, differentiation , cell growth and metabolic coordination of avascular organs , including epidermis . 47

48. APPLIED ASPECT Mutations Cx26- Bart pumphrey syndr Palmoplantar keratoderma with deafness 48

49. 30- Cloustons syndrome Atrichia of scalp nail dystrophy diffuse plantar keratoderma 30.3 & 31 Erythrokeratoderma variabilis Oval red scaly plaques- joind -map like 49

50. REFERENCES ROOKS 8 th edition FITZPATRICKS 8 th edition BOLOGNIA 3 rd edition IADVL 4 th edition LEVER’S histopathology 10 th edition 50

51. THANK YOU 51