TY - JOUR
T1 - hsa-miR-424–5p and hsa-miR-513c-3p dysregulation mediated by IFN-γ is associated with salivary gland dysfunction in Sjögren's syndrome patients
AU - Carvajal, Patricia
AU - Aguilera, Sergio
AU - Jara, Daniela
AU - Indo, Sebastián
AU - Barrera, María José
AU - González, Sergio
AU - Molina, Claudio
AU - Heathcote, Benjamín
AU - Hermoso, Marcela
AU - Castro, Isabel
AU - González, María Julieta
N1 - Funding Information:
This work was supported by Fondecyt -Chile [ 1210055 to MJG, SA, IC, CM, SG, MJB; 1160015 to MJG, SA, IC, CM, SG], Enlace-VID Universidad de Chile [ ENL04/20 to MJG]; FONDAP [ 15130011 to MH]; Fondecyt -Iniciación [ 11201058 to MJB]; and PhD fellowship Conicyt -Chile to PC and DJ.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/7
Y1 - 2023/7
N2 - Salivary secretory dysfunction in SS-patients is associated with altered proteostasis, upregulation of ATF6α and components of the ERAD complex, such as SEL1L, and downregulation of XBP-1s and GRP78. Hsa-miR-424–5p is downregulated and hsa-miR-513c-3p is overexpressed in salivary glands from SS-patients. These miRNAs emerged as candidates that could regulate ATF6/SEL1L and XBP-1s/GRP78 levels, respectively. This study aimed to evaluate the effect of IFN-γ on hsa-miR-424–5p and hsa-miR-513c-3p expression and how these miRNAs regulate their targets. In labial salivary glands (LSG) biopsies from 9 SS-patients and 7 control subjects and IFN-γ-stimulated 3D-acini were analyzed. hsa-miR-424–5p and hsa-miR-513c-3p levels were measured by TaqMan assays and their localization by ISH. mRNA, protein levels, and localization of ATF6, SEL1L, HERP, XBP-1s and GRP78 were determined by qPCR, Western blot, or immunofluorescence. Functional and interaction assays were also performed. In LSGs from SS-patients and IFN-γ-stimulated 3D-acini, hsa-miR-424–5p was downregulated and ATF6α and SEL1L were upregulated. ATF6α and SEL1L were decreased after hsa-miR-424–5p overexpression, while ATF6α, SEL1L and HERP increased after hsa-miR-424–5p silencing. Interaction assays revealed that hsa-miR-424–5p targets ATF6α directly. hsa-miR-513c-3p was upregulated and XBP-1s and GRP78 were downregulated. XBP-1s and GRP78 were decreased after hsa-miR-513c-3p overexpression, while increases in XBP-1s and GRP78 were observed after hsa-miR-513c-3p silencing. Furthermore, we determined that hsa-miR-513c-3p targets XBP-1s directly. Significant correlations were found between both miRNA levels and clinical parameters. In conclusion, IFN-γ-dependent hsa-miR-424–5p and hsa-miR-513c-3p levels affect the expression of important factors involved in cellular proteostasis that control secretory function in LSG from SS-patients.
AB - Salivary secretory dysfunction in SS-patients is associated with altered proteostasis, upregulation of ATF6α and components of the ERAD complex, such as SEL1L, and downregulation of XBP-1s and GRP78. Hsa-miR-424–5p is downregulated and hsa-miR-513c-3p is overexpressed in salivary glands from SS-patients. These miRNAs emerged as candidates that could regulate ATF6/SEL1L and XBP-1s/GRP78 levels, respectively. This study aimed to evaluate the effect of IFN-γ on hsa-miR-424–5p and hsa-miR-513c-3p expression and how these miRNAs regulate their targets. In labial salivary glands (LSG) biopsies from 9 SS-patients and 7 control subjects and IFN-γ-stimulated 3D-acini were analyzed. hsa-miR-424–5p and hsa-miR-513c-3p levels were measured by TaqMan assays and their localization by ISH. mRNA, protein levels, and localization of ATF6, SEL1L, HERP, XBP-1s and GRP78 were determined by qPCR, Western blot, or immunofluorescence. Functional and interaction assays were also performed. In LSGs from SS-patients and IFN-γ-stimulated 3D-acini, hsa-miR-424–5p was downregulated and ATF6α and SEL1L were upregulated. ATF6α and SEL1L were decreased after hsa-miR-424–5p overexpression, while ATF6α, SEL1L and HERP increased after hsa-miR-424–5p silencing. Interaction assays revealed that hsa-miR-424–5p targets ATF6α directly. hsa-miR-513c-3p was upregulated and XBP-1s and GRP78 were downregulated. XBP-1s and GRP78 were decreased after hsa-miR-513c-3p overexpression, while increases in XBP-1s and GRP78 were observed after hsa-miR-513c-3p silencing. Furthermore, we determined that hsa-miR-513c-3p targets XBP-1s directly. Significant correlations were found between both miRNA levels and clinical parameters. In conclusion, IFN-γ-dependent hsa-miR-424–5p and hsa-miR-513c-3p levels affect the expression of important factors involved in cellular proteostasis that control secretory function in LSG from SS-patients.
KW - IFN-γ
KW - Proteostasis
KW - Salivary-epithelial-cells
KW - Secretory dysfunction
KW - Sjögren's syndrome
KW - microRNAs
UR - http://www.scopus.com/inward/record.url?scp=85159685152&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2023.103037
DO - 10.1016/j.jaut.2023.103037
M3 - Article
C2 - 37229808
AN - SCOPUS:85159685152
SN - 0896-8411
VL - 138
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
M1 - 103037
ER -