Dataset Information

UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-?B Signaling.

ABSTRACT: Although over 40 type 1 diabetes (T1D) risk loci have been mapped in humans, the causative genes and variants for T1D are largely unknown. Here, we investigated a candidate gene in the 21q22.3 risk locus-UBASH3A, which is primarily expressed in T cells where it is thought to play a largely redundant role. Genetic variants in UBASH3A have been shown to be associated with several autoimmune diseases in addition to T1D. However, the molecular mechanism underlying these genetic associations is unresolved. Our study reveals a previously unrecognized role of UBASH3A in human T cells: UBASH3A attenuates the NF-?B signal transduction upon T-cell receptor (TCR) stimulation by specifically suppressing the activation of the I?B kinase complex. We identify novel interactions of UBASH3A with nondegradative polyubiquitin chains, TAK1 and NEMO, suggesting that UBASH3A regulates the NF-?B signaling pathway by an ubiquitin-dependent mechanism. Finally, we show that risk alleles at rs11203203 and rs80054410, two T1D-associated variants in UBASH3A, increase UBASH3A expression in human primary CD4+ T cells upon TCR stimulation, inhibiting NF-?B signaling via its effects on the I?B kinase complex and resulting in reduced IL2 gene expression.

SUBMITTER: Ge Y

PROVIDER: S-EPMC5482087 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling.

Ge Yan Y Paisie Taylor K TK Newman Jeremy R B JRB McIntyre Lauren M LM Concannon Patrick P

Diabetes 20170612 7

Although over 40 type 1 diabetes (T1D) risk loci have been mapped in humans, the causative genes and variants for T1D are largely unknown. Here, we investigated a candidate gene in the 21q22.3 risk locus-<i>UBASH3A</i>, which is primarily expressed in T cells where it is thought to play a largely redundant role. Genetic variants in <i>UBASH3A</i> have been shown to be associated with several autoimmune diseases in addition to T1D. However, the molecular mechanism underlying these genetic associa ...[more]

PMID: 28607106

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Dataset Information

UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-?B Signaling.

Publications

UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling.

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