The single
nucleotide polymorphism rs7804356 located in the Src kinase-associated
phosphoprotein 2<i> </i>(SKAP2) gene<i> </i>is associated with type 1 diabetes
(T1D) suggesting <i>SKAP2</i> as a causal
candidate gene. The objective of the study was to investigate if SKAP2 has a
functional role in the β-cells in relation to T1D. In a cohort of children with
newly diagnosed T1D, rs7804356 predicted glycaemic control and residual β-cell
function during first year after diagnosis. In INS-1E cells and rat and human
islets, pro-inflammatory cytokines reduced the content of SKAP2. Functional
studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis
in INS-1E cells and primary rat b-cells, suggesting an anti-apoptotic function of
SKAP2. In support of this, overexpression of SKAP2 afforded protection against
cytokine-induced apoptosis which correlated with reduced nuclear content of
S536-phosphorylated NFκB subunit p65, lower nitric oxide production and diminished
C/EBP-homologues protein (CHOP) expression indicative of decreased endoplasmic
reticulum stress. Knockdown of CHOP partially counteracted the increase in
cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our
results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by
affecting the NFκB-iNOS-ER stress pathway.
BACH2, a Candidate Risk Gene for Type 1 Diabetes, Regulates Apoptosis in Pancreatic -Cells via JNK1 Modulation and Crosstalk With the Candidate Gene PTPN2