The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells
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The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells. / Floyel, Tina; Mirza, Aashiq Hussain; Kaur, Simranjeet; Frorup, Caroline; Yarani, Reza; Storling, Joachim; Pociot, Flemming.
In: Molecular and Cellular Endocrinology, Vol. 518, 110993, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells
AU - Floyel, Tina
AU - Mirza, Aashiq Hussain
AU - Kaur, Simranjeet
AU - Frorup, Caroline
AU - Yarani, Reza
AU - Storling, Joachim
AU - Pociot, Flemming
PY - 2020
Y1 - 2020
N2 - The type 1 diabetes (T1D) risk locus on chromosome 15q25.1 harbors the candidate gene CTSH (cathepsin H). We previously demonstrated that CTSH regulates beta-cell function in vitro and in vivo. CTSH overexpression protected insulin-secreting INS-1 cells against cytokine-induced apoptosis. The purpose of the present study was to identify the genes through which CTSH mediates its protective effects. Micmarray analysis identified 63 annotated genes differentially expressed between CTSH-overexpressing INS-1 cells and control cells treated with interleukin-1 beta and interferon-gamma for up to 16h. Permutation test identified 10 significant genes across all timepoints: Elmod1, Fam49a, Gas7, Gnal5, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified the "Inflammation mediated by chemokine and cytokine signaling pathway" with Gnal5, Ptgs1 and Rac2 as significant. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis, suggesting that the small GTPase and T1D candidate gene Rac2 contributes to the anti-apoptotic effect of CTSH.
AB - The type 1 diabetes (T1D) risk locus on chromosome 15q25.1 harbors the candidate gene CTSH (cathepsin H). We previously demonstrated that CTSH regulates beta-cell function in vitro and in vivo. CTSH overexpression protected insulin-secreting INS-1 cells against cytokine-induced apoptosis. The purpose of the present study was to identify the genes through which CTSH mediates its protective effects. Micmarray analysis identified 63 annotated genes differentially expressed between CTSH-overexpressing INS-1 cells and control cells treated with interleukin-1 beta and interferon-gamma for up to 16h. Permutation test identified 10 significant genes across all timepoints: Elmod1, Fam49a, Gas7, Gnal5, Msrb3, Nox1, Ptgs1, Rac2, Scn7a and Ttn. Pathway analysis identified the "Inflammation mediated by chemokine and cytokine signaling pathway" with Gnal5, Ptgs1 and Rac2 as significant. Knockdown of Rac2 abolished the protective effect of CTSH overexpression on cytokine-induced apoptosis, suggesting that the small GTPase and T1D candidate gene Rac2 contributes to the anti-apoptotic effect of CTSH.
KW - Type 1 diabetes
KW - Beta cell
KW - Inflammation
KW - Cell death
KW - CTSH
KW - Microarray
KW - GENOME-WIDE ASSOCIATION
KW - HUMAN PANCREATIC-ISLETS
KW - CANDIDATE GENES
KW - NITRIC-OXIDE
KW - REACTIVE OXYGEN
KW - EXPRESSION
KW - CYCLOOXYGENASE-2
KW - INFLAMMATION
KW - ACTIVATION
KW - PATHOGENESIS
U2 - 10.1016/j.mce.2020.110993
DO - 10.1016/j.mce.2020.110993
M3 - Journal article
C2 - 32814070
VL - 518
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
M1 - 110993
ER -
ID: 256986062