POS0100 ACTIVATION OF THE CELLULAR INTEGRATED STRESS RESPONSE IN LABIAL SALIVARY GLANDS FROM SJÖGREN’S SYNDROME PATIENTS.

Background Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by inflammation of the exocrine glands and severe symptoms eye mouth dryness. Disorders in saliva secretion process have been associated with oxidative endoplasmic reticulum (ER) stress combination inflammatory responses. The integrated response (ISR) mechanism that allows cells to modify their gene expression program restore homeostasis promote survival against various extrinsic intrinsic signals, such as hypoxia, nutrient deprivation, viral infections, factors (cytokines, chemokines, inflammasomes), accumulation unfolded proteins ER, among others (1). ISR regulated four kinases: PERK, PKR, HRI GCN2, dimerize autophosphorylate become active each one responds different stimuli. signaling pathways are activated stimulate phosphorylation eIF2α, which causes transient inhibition global protein synthesis induction some specific genes like ATF4 NRF2. induces transcription involved metabolism uptake, redox status, regulation apoptosis. Dephosphorylation eIF2α termination signal mediated PP1 complex, recruits catalytic subunit PP1c its two regulatory subunits: GADD34 or CREP. Objectives To evaluate presence functional state (phosphorylation) sensing GCN2; levels /p-eIF2α key NRF2, well subunits complex termination: PP1c, CREP labial salivary (LSG) SS-patients. Methods Biopsies LSG from 12 SS-patients 11 control subjects were studied. mRNA, phospho (p)-protein components determined RT-qPCR Western blotting. Results Our results show increased p-PERK/PERK ratio (11/11), PKR (7/11), p-PKR p-PKR/PKR (5/11), p-eIF2α (5/11) (11/11) compared subjects. No significant changes found mRNA HRI, between Decreased (8/12), p-GCN2 (6/11), NRF2 (11/12), p-NRF2 (12/12) showing scarce parenchyma high fibrosis fat infiltration. On other hand, showed decreased all LSG. Interestingly, Ro autoantibodies focus score negatively correlated whereas positively levels. Conclusion overexpression activation kinases together decrease PP1c/CREP phosphatase suggests continuous ISR, resulting remain This would explain target antioxidant SS patients suggesting plays role pro-survival cellular stress. References [1]Pakos-Zebrucka K, Koryga I, Mnich Ljujic M, Samali A, Gorman AM. response. EMBO Rep. 2016;17(10):1374-95. Acknowledgements work was supported Fondecyt-Chile 1210055; Enlace-VID Universidad de Chile [ENL04/20 MJG]; Fondecyt Iniciacion 11201058 PhD fellowship Conicyt Chile. Disclosure Interests None declared