ライフサイエンスコーパス: ZnT8

1 antigens, such as insulin, IA-2 and Slc30a8 (ZnT8).

2 ed protein 2 (IA-2), and zinc transporter 8 (ZnT8).

3 secretory granule-enriched zinc transporter, ZnT8.

4 ed zinc accumulation through the transporter ZnT8.

5 ly, reversibly, and gradually down-regulated ZnT8.

6 ly expressed a tagged human zinc transporter ZnT8.

7 f a beta-cell specific zinc ion transporter, ZnT8.

8 tigens including two polymorphic variants of ZnT8.

9 soned that this would likely be the case for ZnT8.

10 2) to determine whether zinc transporter 8 (ZnT8), a recently described target of autoantibodies in

11 s to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis.

12 common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans,

13 peutic interventions because the response to ZnT8 administration could be protective or immunogenic d

14 toantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R,

15 mAb43 protects the extracellular epitope of ZnT8 against immunolabeling by serum ICSA from a patient

16 l surface, masking the antigenic exposure of ZnT8 and insulin after glucose-stimulated insulin secret

17 easome activation that coordinately degraded ZnT8 and insulin over a 1,000-fold cytokine concentratio

18 The abundant surface display of endogenous ZnT8 and its coupling to GSIS demonstrated the potential

19 A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associa

20 ns, islet autoantibodies against GAD65, IA2, ZnT8, and beta-cell function.

21 ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects

22 e domain that is accessible to extracellular ZnT8 antibody (ZnT8A).

23 Here we show that a membrane-embedded human ZnT8 antigen triggered a vigorous immune response in ZnT

24 Loss-of-function mutations in ZnT8 are associated with protection against type-2 diabe

25 ding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results s

26 g the secretory granule Zn(2)(+) transporter ZnT8, are associated with type 2 diabetes risk.

27 A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide chan

28 Identifying ZnT8 as a major antigenic target of ICSA allows for rese

29 upling to GSIS demonstrated the potential of ZnT8 as a surface biomarker for tracking and isolating f

30 These data position ZnT8 as an appealing target for treatment aimed at maint

31 Here, we developed an in-cell ZnT8 assay to track endogenous ZnT8 responses to metabol

32 ts in SLC30A8, encoding the zinc transporter ZnT8, associated with diabetes risk.

33 ng aa(325) lies within the region of highest ZnT8 autoantibody (ZnT8A) binding, prompting an investig

34 It argues against ZnT8 autoimmunity arising from molecular mimicry and sug

35 It is not clear whether ZnT8 can be displayed on the cell surface and how insuli

36 clonal antibody (mAb43) against cell-surface ZnT8 could home in on pancreatic islets and prevent auto

37 g immunoproteasomes blocked cytokine-induced ZnT8 degradation and triggered a transition of the adapt

38 the primary target of the cytokine-mediated ZnT8 down-regulation.

39 ere we examined for CD4 T-cell reactivity to ZnT8 epitopes in the NOD mouse.

40 Some single ZnT8 epitopes performed as well as the group of epitopes

41 2(+) children with diabetes, 29 responded to ZnT8 epitopes, whereas only 3 of 16 HLA-A2(+) control pa

42 d mice, we identified nine HLA-A2-restricted ZnT8 epitopes.

43 insulin secretion may regulate the level of ZnT8 exposure to extracellular immune surveillance.

44 Moreover, the variation in tagged-ZnT8 expression and surface labeling enabled sorting of

45 aled strong correlations among the levels of ZnT8 expression, its display on the cell surface, and gl

46 ZnT2 expression, and PEDF increased ZnT3 and ZnT8 expression.

47 in GSIS with parallel changes in endogenous ZnT8 expression.

48 increased the surface display of endogenous ZnT8 from a basal level to 32.5% of the housekeeping Na(

49 tations in the zinc efflux transport protein ZnT8 have been linked with both type 1 and type 2 diabet

50 e, we report the cryo-EM structures of human ZnT8 (HsZnT8) in both outward- and inward-facing conform

51 , and ZIP10 in metastatic breast cancer, and ZnT8 in insulin processing and as an autoantigen in diab

52 is, IFN-gamma-producing T cells specific for ZnT8 in the peripheral blood of 35 patients with T1D (<6

53 let antigen-2 (IA-2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes.

54 sufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevent

55 Our results demonstrate that ZnT8 is a cell surface self-antigen, raising the possibi

56 Thus, ZnT8 is a major CD8(+) T-cell autoantigen, and ELISpot a

57 The islet-specific zinc transporter ZnT8 is a major self-antigen found in insulin granules o

58 We conclude that in NOD mice, ZnT8 is a minor diabetogenic antigen that can participat

59 ZnT8 is a Zn(2+)/H(+) antiporter that belongs to SLC30 f

60 We conclude that ZnT8 is also a major target of disease-associated autore

61 ZnT8 is mostly expressed in pancreatic insulin-producing

62 ZnT8 is thus important in a subset of alpha-cells for no

63 Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the b

64 tly we demonstrated that zinc transporter 8 (ZnT8) is a major target of autoantibodies in human type

65 e SLC30A8 gene encoding the zinc transporter ZnT8, is associated with an increased risk for T2DM.

66 f the beta-cell-specific Zn(2+) transporter, ZNT8, is linked to T2DM susceptibility.

67 igen triggered a vigorous immune response in ZnT8 knock-out mice.

68 ZnT8A bound to live INS-1E cells, whereas a ZnT8 knock-out specifically reduced the surface binding.

69 city was validated by a CRISPR/Cas9 mediated ZnT8 knock-out.

70 RNAi-mediated ZnT8 knockdown protected cells against cytokine cytotoxi

71 SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet beta- and al

72 , cytokine-induced down-regulation of the ER ZnT8 level promotes adaptive UPR, acting as a protective

73 and free fatty acids did not alter cellular ZnT8 levels, but proinflammatory cytokines acutely, reve

74 toantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 +/- 3.7 years; and 1

75 The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions.

76 The islet-specific zinc transporter ZnT8 mediates zinc enrichment in the insulin secretory g

77 Knockout of the Zn(2)(+) transporter ZnT8 (ZnT8(-/-) mice) did not prevent the glucagonostatic effe

78 oding syntaxin 1A but decreased Munc18-1 and ZnT8 mRNA.

79 ore, zinc deficiency due to loss-of-function ZnT8 mutations shifts insulin oligomer equilibrium towar

80 alpha-cells, of which approximately 50% were ZnT8-negative (14 +/- 1.8% of all alpha-cells).

81 ZnT8 null mice have a mild phenotype with a slight decre

82 Zinc transporter-8 (ZnT8) primarily functions as a zinc-sequestrating transp

83 iate with T2D protection and encode unstable ZnT8 proteins.

84 ) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA.

85 e ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed between immigrant and Swedish

86 simulation showed nonbinding of the relevant ZnT8-R peptide to DQ2, explaining in part a possible lac

87 ning in part a possible lack of tolerance to ZnT8-R.

88 glucose tolerance, whereas patients with the ZnT8 R325W polymorphism (rs13266634) have decreased proi

89 ZnT8-RA (57 and 58%, respectively) did not differ despit

90 At diagnosis in non-Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of

91 ransporter 8 autoantibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA varia

92 associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA.

93 culture assay indicated the weak transfer of ZnT8 reactivity from insulinomas or primary beta-cells t

94 wever, the Zn(2+)/H(+) exchange mechanism of ZnT8 remains unclear due to the lack of high-resolution

95 umoral antigenicity of the surface-displayed ZnT8 remains unknown.

96 ed an in-cell ZnT8 assay to track endogenous ZnT8 responses to metabolic and inflammatory stresses ap

97 oantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of ins

98 for a GSIS-dependent surface exposure of the ZnT8 self-antigen.

99 ibodies to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identi

100 high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80%

101 ells in three adults and zinc transporter 8 (ZnT8)-specific CD4(+) T cells in five adults.

102 rated assay to determine whether the type of ZnT8-specific CD4(+) T cells is different between Type 1

103 We found that ZnT8-specific CD4(+) T cells were skewed towards Th1 cel

104 1D, and we suggest that reagents that target ZnT8-specific T cells could have therapeutic potential i

105 e mechanism that decongests the ER burden of ZnT8 to protect beta-cells from proapoptotic UPR during

106 Frequent insulin secretion exposes ZnT8 to the cell surface, but the humoral antigenicity o

107 of ZnT8A specific or cross-reactive with the ZnT8 tryptophan-325 polymorphic residue, but not those s

108 activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325).

109 Purified ZnT8 variants in proteoliposomes exhibited more than 4-f

110 Non-Swedes had less frequent ZnT8-WA (38%) than Swedes (50%), consistent with a lower

111 /X (2/2; 2/y) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA.

112 -Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of HLA-DQ2 and the SLC

113 ibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed betwee

114 Approximately 50% of the cellular ZnT8 was localized to the endoplasmic reticulum (ER), wh

115 te decarboxylase (GADA), IA-2, IA-2beta, and ZnT8 were analyzed in samples collected from patients wi

116 ately 50% of serum immunoreactivities toward ZnT8 were mapped to its transmembrane domain that is acc

117 abetes-related autoantibody (GADA, IA-2A, or ZnT8) were randomly assigned by a web-based randomisatio

118 SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into i

119 in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects ag

120 43) that recognizes a major T1D autoantigen, ZnT8, with a subnanomolar binding affinity and conformat

121 Knockout of the Zn(2)(+) transporter ZnT8 (ZnT8(-/-) mice) did not prevent the glucagonostati

122 sulin (IAA), GAD65 (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A).

123 insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays.