@article{1d793e367a964e648681bd06e87694cf,
title = "Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction",
abstract = "Age-associated decay of intercellular interactions impairs the cells{\textquoteright} capacity to tightly associate within tissues and form a functional barrier. This barrier dysfunction compromises organ physiology and contributes to systemic failure. The actin cytoskeleton represents a key determinant in maintaining tissue architecture. Yet, it is unclear how age disrupts the actin cytoskeleton and how this, in turn, promotes mortality. Here, we show that an uncharacterized phosphorylation of a low-abundant actin variant, ACT-5, compromises integrity of the C. elegans intestinal barrier and accelerates pathogenesis. Age-related loss of the heat-shock transcription factor, HSF-1, disrupts the JUN kinase and protein phosphatase I equilibrium which increases ACT-5 phosphorylation within its troponin binding site. Phosphorylated ACT-5 accelerates decay of the intestinal subapical terminal web and impairs its interactions with cell junctions. This compromises barrier integrity, promotes pathogenesis, and drives mortality. Thus, we provide the molecular mechanism by which age-associated loss of specialized actin networks impacts tissue integrity.",
keywords = "HSF-1, actin, aging, barrier, intestine, junctions, kinase, pathogenesis, phosphorylation, stress",
author = "Nathan Egge and Arneaud, {Sonja L.B.} and Pauline Wales and Melina Mihelakis and Jacob McClendon and Fonseca, {Rene Solano} and Charles Savelle and Ian Gonzalez and Atossa Ghorashi and Sivaramakrishna Yadavalli and Lehman, {William J.} and Hamid Mirzaei and Douglas, {Peter M.}",
note = "Funding Information: We are thankful for support for this work from the Welch Foundation ( I-1920-20170325 to P.M.D.), the American Federation of Aging Research , the Glenn Center for Aging , the NIH ( R00AG042495 and R01AG061338 to P.M.D. as well as R01HL036153 to W.J.L.), and the Cancer Prevention Research Institute of Texas (CPRIT) ( RR150089 to P.M.D.). We appreciate the Caenorhabditis Genetic Center (CGC) for worm strains. We thank the UTSW Electron Microscopy Core Facility for all of our EM work and the UTSW Proteomics Core Facility for all of our LC-MS/MS analyses. We appreciate open access RNA-seq datasets published by the Westerheide lab ( Brunquell et al., 2016 ). We thank Dr. Emily Troemel for the GFP::ACT-5 plasmid and worm strains ( Szumowski et al., 2016 ). We thank Dr. Kevin O{\textquoteright}Connell for the GSP-1 antibody. We thank the Sato laboratory for the mCherry::ACT-5 worm strain. We thank Dr. Michael Shapira for discussion and insight regarding the JUN kinase, KGB-1. We appreciate Drs. Ryo Higuchi-Sanabria and Andrew Dillin for providing the LifeAct::mRuby worm strains, Dr. Ryan Hibbs for structural modeling assistance, and Dr. Neil Alto for the fluorescent E. coli expression plasmids, pDP151. We thank Dr. Vincent Tagliabracci for the recombinant, YopH phosphatase. We appreciate critical feedback from Drs. Michael Rosen, Michael Buszczak, and Michael Douglas. We thank Jose Cabrera for assistance with graphic models. We thank McKay et al., (WBPaper00006525) for worm strains. Funding Information: We are thankful for support for this work from the Welch Foundation (I-1920-20170325 to P.M.D.), the American Federation of Aging Research, the Glenn Center for Aging, the NIH (R00AG042495 and R01AG061338 to P.M.D. as well as R01HL036153 to W.J.L.), and the Cancer Prevention Research Institute of Texas (CPRIT) (RR150089 to P.M.D.). We appreciate the Caenorhabditis Genetic Center (CGC) for worm strains. We thank the UTSW Electron Microscopy Core Facility for all of our EM work and the UTSW Proteomics Core Facility for all of our LC-MS/MS analyses. We appreciate open access RNA-seq datasets published by the Westerheide lab (Brunquell et al. 2016). We thank Dr. Emily Troemel for the GFP::ACT-5 plasmid and worm strains (Szumowski et al. 2016). We thank Dr. Kevin O'Connell for the GSP-1 antibody. We thank the Sato laboratory for the mCherry::ACT-5 worm strain. We thank Dr. Michael Shapira for discussion and insight regarding the JUN kinase, KGB-1. We appreciate Drs. Ryo Higuchi-Sanabria and Andrew Dillin for providing the LifeAct::mRuby worm strains, Dr. Ryan Hibbs for structural modeling assistance, and Dr. Neil Alto for the fluorescent E. coli expression plasmids, pDP151. We thank Dr. Vincent Tagliabracci for the recombinant, YopH phosphatase. We appreciate critical feedback from Drs. Michael Rosen, Michael Buszczak, and Michael Douglas. We thank Jose Cabrera for assistance with graphic models. We thank McKay et al. (WBPaper00006525) for worm strains. Conceptualization, N.E. P.W. and P.M.D.; Methodology, N.E. S.L.B.A. P.W. M.M. J.M. C.S. I.G. A.G. S.Y. W.J.L, H.M. and P.M.D.; Investigation, N.E. S.L.B.A. P.W. M.M. R.S.F. J.M. C.S. and I.G.; Writing ? Review & Editing, P.M.D. N.E. S.L.B.A. and W.J.L.; Funding Acquisition, Resources, & Supervision, P.M.D. H.M. and W.J.L. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "2",
doi = "10.1016/j.devcel.2019.11.001",
language = "English (US)",
volume = "51",
pages = "587--601.e7",
journal = "Developmental cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "5",
}