ライフサイエンスコーパス: ZnT8

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

2 ly expressed a tagged human zinc transporter ZnT8.

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

4 tigens including two polymorphic variants of ZnT8.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

26 2(+) children with diabetes, 29 responded to ZnT8 epitopes, whereas only 3 of 16 HLA-A2(+) control pa

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

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

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

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

31 in GSIS with parallel changes in endogenous ZnT8 expression.

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

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

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

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

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

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

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

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

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

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

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

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

44 ZnT8 is mostly expressed in pancreatic insulin-producing

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

61 iate with T2D protection and encode unstable ZnT8 proteins.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

79 1D, and we suggest that reagents that target ZnT8-specific T cells could have therapeutic potential i

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

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

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

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

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

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

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

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

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

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

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

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

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