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Ningning Wang, Ronald Raab, Robert McKown, Cindy Hutnik, Gordon Laurie; Lacritin as the Primary Epithelial Survival Activity in Basal Human Tears Reveals Novel Features About Autophagic Survival Signaling. Invest. Ophthalmol. Vis. Sci. 2013;54(15):909.
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As the fluid thought to support the survival of the avascular corneal epithelium, tears are rich in proteins with growth and survival capabilities - including lacritin, a tear prosecretory mitogen that supports the survival of stressed corneal epithelial cells in culture, and promotes basal tearing in rabbits and monkeys. Here we ask whether tears are indeed prosurvival, if so does tear lacritin contribute, and what is the FOXO3 survival mechanism?
Human corneal epithelial (HCE; Riken) cells were sensitized with INFG, and then treated with TNF in the in the presence of normal or dry eye tears, normal tears mock or lacritin immunodepleted, or with dry eye tears supplemented with recombinant lacritin or negative control C-25. FOXO3 translocation served as a readout for cell stress (nuclear) or survival (cytoplasmic). FOXO3 immunoprecipitates were used to screen for FOXO3 binding partners.
Normal and mock depleted tears, but not lacritin depleted tears promoted the survival of INFG/TNF stressed HCE cells. Tears from dry eye patients supplemented lacritin promoted cell survival, but not dry eye tears alone nor C-25 supplemented dry eye tears. We discovered that autophagy mediator ATG101 binds FOXO3 in stressed cells treated with lacritin, and that shRNA depletion of ATG101 or FOXO3 abrogates lacritin stimulated autophagy and survival.
Lacritin appears to be the primary survival factor in basal human tears. Surprisingly it is not compensated by other tear factors when depleted. Lack of dry eye tear survival activity can be rescued with recombinant lacritin, suggesting efficacy in treating human dry eye. Lacritin rapidly stimulates FOXO3/ATG101 ligation. ATG101 is known to bind and stabilize the ATG13/ULK1 complex responsible for initiating autophagy - thus explaining how lacritin so rapidly stimulates autophagy.
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