ライフサイエンスコーパス: Dsg1

1 Dsg1 (desmoglein 1) is a member of the cadherin family o

2 Dsg1 lacking N-terminal ectodomain residues required for

3 Dsg1.myc, but not Dsc1a, Dsc1b, disrupted desmosome asse

4 odies against desmoglein 3 and desmoglein 1 (Dsg1) are relevant in the pathogenesis of pemphigus vulg

5 enic, predominantly IgG4, anti-desmoglein 1 (Dsg1) autoantibodies and is endemic in Limao Verde, Braz

6 s (PF), autoantibodies against desmoglein 1 (Dsg1) cause blisters.

7 y response to the self-antigen desmoglein 1 (Dsg1) cross-reacts with the LJM11 sand fly salivary glan

8 Desmoglein 1 (Dsg1) is a desmosomal cadherin that is essential to epid

9 city to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extra

10 se caused by autoantibodies to desmoglein 1 (Dsg1) that cause loss of epidermal cell adhesion.

11 associated proteins, including desmoglein 1 (Dsg1), desmocollin 1 (Dsc1), and keratins 1 and 10 (K1/K

12 Dsc1a, and to a lesser extent, desmoglein 1 (Dsg1), while PG binds to Dsg1 and more weakly to Dsc1a a

13 tracellular domains 3 and 4 of desmoglein 1 (Dsg1).

14 ic IgG4 autoantibodies against desmoglein 1 (Dsg1).

15 desmosomal cadherin component desmoglein 1 (Dsg1).

16 blistering and pathogenic anti-desmoglein-1 (Dsg1) autoantibodies.

17 cadherins to mediate adhesion, desmoglein-1 (Dsg1), desmocollin-2 (Dsc2a) and plakoglobin were expres

18 es are desmoglein-3 (Dsg3) and desmoglein-1 (Dsg1), respectively.

19 against the desmosomal antigen desmoglein-1 (Dsg1).

20 e desmosomal core glycoprotein desmoglein-1 (Dsg1).

21 nst a desmosomal glycoprotein, desmoglein-1 (Dsg1).

22 rs of differentiation (such as desmoglein-1 [Dsg1], keratin-1, and loricrin) and abrogated MAL/SRF si

23 inst desmoglein 3 (Dsg3) and/or desmoglein 1(Dsg1).

24 F) possess pathogenic IgG anti-desmoglein 1-(Dsg1) autoantibodies.

25 t and specific autoantibody response against Dsg1 and other keratinocyte cadherins in these individua

26 ace adhesion proteins desmoglein (Dsg) 3 and Dsg1.

27 Dsg3 and Dsg1 are members of the desmoglein subfamily of the cadh

28 aris patients after incubation with Dsg3 and Dsg1 fusion proteins.

29 PV autoantibodies bind Dsg3 or both Dsg3 and Dsg1.

30 characterized by autoantibodies to Dsg3 and Dsg1.

31 ding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1.

32 al adhesion proteins desmoglein 3 (Dsg3) and Dsg1.

33 Coexpression of Dsc1a.myc or Dsc1b.myc and Dsg1.myc did not lead to their colocalization and failed

34 In contrast, Dsc1a.myc, Dsc1b.myc, and Dsg1.myc did not stably incorporate into desmosomes in a

35 Anti-Dsg1 monoclonal autoantibodies derived from FS patients

36 on of the heavy-chain gene usage of all anti-Dsg1 clones to only five genes, which determined their i

37 e correlation between these indexes and anti-Dsg1 and anti-Dsg3 enzyme-linked immunosorbent assay val

38 subset of PF patients who only express anti-Dsg1 of the IgG1 isotype throughout the course of their

39 ) where Dsg1 without Dsg3 is expressed, anti-Dsg1 antibodies alone can cause blisters.

40 Mice immunized with LJM11 generate anti-Dsg1 Abs.

41 ensitivity, specificity, and PPV of IgG anti-Dsg1 were 87, 91, and 23%, respectively.

42 IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in 2.9% (age 5-10 years), 7.3% (age 11

43 cterize the pathogenicity of their IgG1 anti-Dsg1.

44 Previously, we found that the IgG4 anti-Dsg1 autoantibodies only recognize a conformational epit

45 m LV (n=99, age 5-20 years) possess IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in

46 We propose that IgM anti-Dsg1 are common in FS patients in their native environme

47 IgM anti-Dsg1 epitopes are Ca2+ and carbohydrate-independent.

48 IgM anti-Dsg1 were detected in 58% FS LV patients (n=31), 19% of

49 High percentages of positive IgM anti-Dsg1 were found in healthy donors from four rural Amerin

50 ology, we used phage display to isolate anti-Dsg1 mAbs as single-chain variable fragments (scFvs) fro

51 rom pemphigus vulgaris patients with no anti-Dsg1 serum reactivity showed a proliferative response to

52 ent were predictors of higher titers of anti-Dsg1.

53 Serum anti-Dsg1 and anti-Dsg3 enzyme-linked immunosorbent assay val

54 These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against t

55 osomal antigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively.

56 As Dsg1 promotes epidermal differentiation in addition to p

57 igen (GalNAc-alpha1-O-Ser/Thr), did not bind Dsg1 and did not show a protective effect against the di

58 O-glycan-specific plant lectin jacalin binds Dsg1 and inhibits the interaction of Dsg1/PF IgG.

59 Over 90% are specific for both Dsg1 and Dsg3 indicating extensive cross-reactivity betw

60 The UVB-induced reduction in both Dsg1 transcript and protein was associated with reduced

61 Our findings suggest that both Dsg1 autoantigen and LJM11 environmental Ag could be the

62 us vulgaris sera have IgG reactivity to both Dsg1 and Dsg3, suggesting that Dsg1 may also participate

63 pemphigus vulgaris patients respond to both Dsg1 and Dsg3.

64 all identified IgG4 mAbs cross-react to both Dsg1 and LJM11 Ags.

65 hese PV patients showed reactivity with both Dsg1 and Dsg3, whereas the remaining four reacted only w

66 Galbeta1-3GalNAcalpha-O-Ser/Thr), also bound Dsg1 and blocked the skin blistering.

67 Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce

68 inocytes because of compensatory adhesion by Dsg1 do not activate p38.

69 214 FS patients and 261 healthy controls by Dsg1 ELISA.

70 and prevents the loss of adhesion induced by Dsg1 truncation.

71 ferentiation through the desmosomal cadherin Dsg1.

72 tive Gal4 depends on an F box protein called Dsg1/Mdm30.

73 uman, ETA binds, but does not cleave, canine Dsg1.

74 n human Dsg1 and either human Dsg3 or canine Dsg1, we show that for cleavage, human-specific amino ac

75 epidermis and mucous membrane that coexpress Dsg1 and Dsg3, antibodies against either desmoglein alon

76 m those patients that exhibited the combined Dsg1/Dsg3 autoantibody reactivity showed a proliferative

77 Here, we show that ectodomain-deleted Dsg1 (Delta381-Dsg1) mimics the toxin-cleaved cadherin,

78 show that ectodomain-deleted Dsg1 (Delta381-Dsg1) mimics the toxin-cleaved cadherin, disrupts desmos

79 tional adhesion in cells expressing Delta381-Dsg1 or treated with exfoliative toxin A.

80 Compared with controls, depleting Dsg1 via short hairpin RNA resulted in further reduction

81 n, in the DSG1 gene coding for a desmoglein (Dsg1), results in the deletion of the first and much of

82 In keratinocytes, several desmoglein (Dsg1-4) and desmocollin (Dsc1-3) isoforms are coexpresse

83 CSN and desmosomal components, Desmoglein1 (Dsg1) and Desmoplakin (Dp), to promote epidermal differe

84 odels, showing that a single mAb can disrupt Dsg1 function to cause disease.

85 herin and the extracellular domain of either Dsg1 or Dsc2a were expressed in L cells.

86 oglein proteins, and demonstrate that either Dsg1 or Dsg3 alone is sufficient to maintain keratinocyt

87 liferative response after exposure to either Dsg1 or Dsg3 fusion proteins.

88 quamous epithelial cells that do not express Dsg1 or Dsc1.

89 xtensive aggregation, but L cells expressing Dsg1 or Dsc2a did not aggregate.

90 In addition, L cells co-expressing Dsg1, Dsc2a, and plakoglobin failed to aggregate.

91 desmoglein (Dsg) 3 and, to a lesser extent, Dsg1.

92 Consistent with this hypothesis, we found Dsg1 and Dsg3 expression overlapping in the companion la

93 or cleavage, human-specific amino acids from Dsg1 are necessary in extracellular domain 3 upstream of

94 However, presentation of peptides from Dsg1 by preDsg1-specific B cells may be one step in deve

95 an Dsg1 and chimeric molecules between human Dsg1 and either human Dsg3 or canine Dsg1, we show that

96 Using truncated mutants of human Dsg1 and chimeric molecules between human Dsg1 and eithe

97 he plakoglobin:E-cadherin ratio decreased in Dsg1-expressing cells with disrupted desmosomes, but a d

98 me mAbs plus exfoliative toxin to inactivate Dsg1 but not exfoliative toxin alone activate p38, sugge

99 used exfoliative toxin A (ETA) to inactivate Dsg1 in Dsg3-/- mice.

100 Instead, Dsg1 was required for suppression of epidermal growth fa

101 evious patient, were directed against mature Dsg1 (matDsg1) on the cell surface of keratinocytes and

102 l cohesion is prevalent in tumor metastasis, Dsg1 integrity was evaluated.

103 DP-NTP binds directly to plakoglobin but not Dsg1.

104 In the absence of Dsg1, Gal4 is stable, nonubiquitylated, and unable to pr

105 ne RNA and protein levels; in the absence of Dsg1, Gal4 target genes are transcribed, but the resulti

106 e restricted to the first 161 amino acids of Dsg1, whereas the linear epitopes are spread throughout

107 yndrome, pathogenesis depends on cleavage of Dsg1 by a bacterial protease, exfoliative toxin A, which

108 Kinetic studies monitoring the cleavage of Dsg1 by ETA, ETB, and ETD demonstrated kcat/Km values of

109 ts show that SCC25 cells exhibit cleavage of Dsg1, which is blocked by proteinase inhibitor treatment

110 we test the hypothesis that coexpression of Dsg1 and Dsg3 in keratinocytes protects against patholog

111 sera and the normal tissue distributions of Dsg1 and Dsg3 determine the sites of blister formation.

112 ised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically

113 epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergenc

114 e in response to the extracellular domain of Dsg1.

115 s on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset.

116 interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked approximately 50% of

117 Ectopic expression of Dsg1 in keratinocyte monolayers rescued the UVB-induced

118 in keratinocytes, and ectopic expression of Dsg1 rescued defects in differentiation seen upon loss o

119 lation is not involved in the interaction of Dsg1/jacalin or Dsg1/PF IgG.

120 n binds Dsg1 and inhibits the interaction of Dsg1/PF IgG.

121 ed that loss of Bcr or MAL reduced levels of Dsg1 mRNA in keratinocytes, and ectopic expression of Ds

122 A reciprocal relationship between loss of Dsg1 and neddylated EGFR was observed in a carcinoma mod

123 isruption correlated with the recruitment of Dsg1.myc, but not Dsc1a or Dsc1b, into a Triton-insolubl

124 icipating in cell-cell adhesion, the role of Dsg1 in aiding differentiation after UVB damage was test

125 ndent on the calcium-stabilized structure of Dsg1.

126 conformational epitopes in the N terminus of Dsg1.

127 acalin to O-linked TF carbohydrate motifs on Dsg1 impairs the Dsg1/PF autoantibody interactions and a

128 ScFv mAbs demonstrated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1.

129 volved in the interaction of Dsg1/jacalin or Dsg1/PF IgG.

130 tely 1:1 stoichiometry; however, plakoglobin:Dsg1 complexes exhibited a 6:1 stoichiometry.

131 aining of A431DE cells (E-cadherin positive, Dsg1 negative) with pemphigus sera showed negative resul

132 cell surface of keratinocytes and precursor Dsg1 (preDsg1) in the cytoplasm.

133 y FS patients in response to endogenous self-Dsg1 and exogenous LJM11 sand fly Ag.

134 These mAbs will be useful for studying Dsg1 function and mechanisms of blister formation in PF

135 We hypothesized that Dsg1 compensates for the loss of Dsg3 in the anagen hair

136 In this study, we show that Dsg1 is not only required for maintaining epidermal tiss

137 ivity to both Dsg1 and Dsg3, suggesting that Dsg1 may also participate in the autoimmune response of

138 The Dsg1 fusion protein used in this study has minimal seque

139 These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment

140 d TF carbohydrate motifs on Dsg1 impairs the Dsg1/PF autoantibody interactions and abrogates its path

141 in A, which removes residues 1 to 381 of the Dsg1 ectodomain.

142 nreported enhancer regulatory regions of the Dsg1 gene.

143 e molecule for cadherin function, and of the Dsg1 protein and hence desmosomes in epidermal function.

144 of the companion layer, and particularly the Dsg1 and Dsg3 in this layer, in anchoring the anagen hai

145 These Dsg1-reactive FS T cells exhibited a CD4-positive memory

146 tent, desmoglein 1 (Dsg1), while PG binds to Dsg1 and more weakly to Dsc1a and DP.

147 a proliferative response to Dsg3, but not to Dsg1.

148 eloped from these patients also responded to Dsg1, and this antigen-specific response was shown to be

149 However, the cellular responses to Dsg1 cleavage that precipitate keratinocyte separation t

150 The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmun

151 s without pemphigus have B cell tolerance to Dsg1, we cloned mAbs from two patients with thrombotic t

152 that plakoglobin sequestration by truncated Dsg1 destabilizes other cadherins.

153 ial to the pathogenic potential of truncated Dsg1.

154 In addition, we demonstrate that truncated Dsg1 remains associated with its catenin partner, plakog

155 superficial epidermis of normal mice) where Dsg1 without Dsg3 is expressed, anti-Dsg1 antibodies alo

156 n 2 (Dsc2), which are widely expressed, with Dsg1 and Dsc1, which are expressed in the differentiated

157 anti-E-cadherin antibodies cross-react with Dsg1, whereas others may represent independent antibodie

158 dent antibodies that do not cross-react with Dsg1.