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Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis

Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, the light refracting and immunoprotective tear film on eyes would collapse. Premature collapse, coupled with chronic inflammation compromising visual acuity, is a hallmark of dr...

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Autores principales: Georgiev, Georgi A., Gh., Mohammad Sharifian, Romano, Jeff, Dias Teixeira, Karina L., Struble, Craig, Ryan, Denise S., Sia, Rose K., Kitt, Jay P., Harris, Joel M., Hsu, Ku-Lung, Libby, Adam, Odrich, Marc G., Suárez, Tatiana, McKown, Robert L., Laurie, Gordon W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948570/
https://www.ncbi.nlm.nih.gov/pubmed/33187980
http://dx.doi.org/10.1074/jbc.RA120.015833
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author Georgiev, Georgi A.
Gh., Mohammad Sharifian
Romano, Jeff
Dias Teixeira, Karina L.
Struble, Craig
Ryan, Denise S.
Sia, Rose K.
Kitt, Jay P.
Harris, Joel M.
Hsu, Ku-Lung
Libby, Adam
Odrich, Marc G.
Suárez, Tatiana
McKown, Robert L.
Laurie, Gordon W.
author_facet Georgiev, Georgi A.
Gh., Mohammad Sharifian
Romano, Jeff
Dias Teixeira, Karina L.
Struble, Craig
Ryan, Denise S.
Sia, Rose K.
Kitt, Jay P.
Harris, Joel M.
Hsu, Ku-Lung
Libby, Adam
Odrich, Marc G.
Suárez, Tatiana
McKown, Robert L.
Laurie, Gordon W.
author_sort Georgiev, Georgi A.
collection PubMed
description Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, the light refracting and immunoprotective tear film on eyes would collapse. Premature collapse, coupled with chronic inflammation compromising visual acuity, is a hallmark of dry eye disease affecting 7 to 10% of individuals worldwide. Although collapse seems independent of mutation (unlike newborn lung alveoli), selective proteome and possible lipidome changes have been noted. These include elevated tissue transglutaminase and consequent inactivation through C-terminal cross-linking of the tear mitogen lacritin, leading to significant loss of lacritin monomer. Lacritin monomer restores homeostasis via autophagy and mitochondrial fusion and promotes basal tearing. Here, we discover that lacritin monomer C-terminal processing, inclusive of cysteine, serine, and metalloproteinase activity, generates cationic amphipathic α-helical proteoforms. Such proteoforms (using synthetic peptide surrogates) act like alveolar surfactant proteins to rapidly bind and stabilize the tear lipid layer. Immunodepletion of C- but not N-terminal proteoforms nor intact lacritin, from normal human tears promotes loss of stability akin to human dry eye tears. Stability of these and dry eye tears is rescuable with C- but not N-terminal proteoforms. Repeated topical application in rabbits reveals a proteoform turnover time of 7 to 33 h with gradual loss from human tear lipid that retains bioactivity without further processing. Thus, the processed C-terminus of lacritin that is deficient or absent in dry eye tears appears to play a key role in preventing tear film collapse and as a natural slow release mechanism that restores epithelial homeostasis.
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spelling pubmed-79485702021-03-19 Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis Georgiev, Georgi A. Gh., Mohammad Sharifian Romano, Jeff Dias Teixeira, Karina L. Struble, Craig Ryan, Denise S. Sia, Rose K. Kitt, Jay P. Harris, Joel M. Hsu, Ku-Lung Libby, Adam Odrich, Marc G. Suárez, Tatiana McKown, Robert L. Laurie, Gordon W. J Biol Chem Research Article Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, the light refracting and immunoprotective tear film on eyes would collapse. Premature collapse, coupled with chronic inflammation compromising visual acuity, is a hallmark of dry eye disease affecting 7 to 10% of individuals worldwide. Although collapse seems independent of mutation (unlike newborn lung alveoli), selective proteome and possible lipidome changes have been noted. These include elevated tissue transglutaminase and consequent inactivation through C-terminal cross-linking of the tear mitogen lacritin, leading to significant loss of lacritin monomer. Lacritin monomer restores homeostasis via autophagy and mitochondrial fusion and promotes basal tearing. Here, we discover that lacritin monomer C-terminal processing, inclusive of cysteine, serine, and metalloproteinase activity, generates cationic amphipathic α-helical proteoforms. Such proteoforms (using synthetic peptide surrogates) act like alveolar surfactant proteins to rapidly bind and stabilize the tear lipid layer. Immunodepletion of C- but not N-terminal proteoforms nor intact lacritin, from normal human tears promotes loss of stability akin to human dry eye tears. Stability of these and dry eye tears is rescuable with C- but not N-terminal proteoforms. Repeated topical application in rabbits reveals a proteoform turnover time of 7 to 33 h with gradual loss from human tear lipid that retains bioactivity without further processing. Thus, the processed C-terminus of lacritin that is deficient or absent in dry eye tears appears to play a key role in preventing tear film collapse and as a natural slow release mechanism that restores epithelial homeostasis. American Society for Biochemistry and Molecular Biology 2020-11-21 /pmc/articles/PMC7948570/ /pubmed/33187980 http://dx.doi.org/10.1074/jbc.RA120.015833 Text en © 2020 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Georgiev, Georgi A.
Gh., Mohammad Sharifian
Romano, Jeff
Dias Teixeira, Karina L.
Struble, Craig
Ryan, Denise S.
Sia, Rose K.
Kitt, Jay P.
Harris, Joel M.
Hsu, Ku-Lung
Libby, Adam
Odrich, Marc G.
Suárez, Tatiana
McKown, Robert L.
Laurie, Gordon W.
Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
title Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
title_full Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
title_fullStr Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
title_full_unstemmed Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
title_short Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
title_sort lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948570/
https://www.ncbi.nlm.nih.gov/pubmed/33187980
http://dx.doi.org/10.1074/jbc.RA120.015833
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