RRC ID 44424
Author Wang N, Zimmerman K, Raab RW, McKown RL, Hutnik CM, Talla V, Tyler MF 4th, Lee JK, Laurie GW.
Title Lacritin rescues stressed epithelia via rapid forkhead box O3 (FOXO3)-associated autophagy that restores metabolism.
Journal J Biol Chem
Abstract Homeostasis is essential for cell survival. However, homeostatic regulation of surface epithelia is poorly understood. The eye surface, lacking the cornified barrier of skin, provides an excellent model. Tears cover the surface of the eye and are deficient in dry eye, the most common eye disease affecting at least 5% of the world's population. Only a tiny fraction of the tear proteome appears to be affected, including lacritin, an epithelium-selective mitogen that promotes basal tearing when topically applied to rabbit eyes. Here we show that homeostasis of cultured corneal epithelia is entirely lacritin-dependent and elucidate the mechanism as a rapid autophagic flux to promptly restore cellular metabolism and mitochondrial fusion in keeping with the short residence time of lacritin on the eye. Accelerated flux appears to be derived from lacritin-stimulated acetylation of FOXO3 as a novel ligand for ATG101 and coupling of stress-acetylated FOXO1 with ATG7 (which remains uncoupled without lacritin) and be sufficient to selectively divert huntingtin mutant Htt103Q aggregates largely without affecting non-aggregated Htt25Q. This is in keeping with stress as a prerequisite for lacritin-stimulated autophagy. Lacritin targets the cell surface proteoglycan syndecan-1 via its C-terminal amino acids Leu(108)-Leu(109)-Phe(112) and is also available in saliva, plasma, and lung lavage. Thus, lacritin may promote epithelial homeostasis widely.
Volume 288(25)
Pages 18146-61
Published 2013-6-21
DOI 10.1074/jbc.M112.436584
PII M112.436584
PMID 23640897
PMC PMC3689958
MeSH Amino Acid Sequence Autophagy / drug effects* Autophagy-Related Protein 7 Autophagy-Related Proteins Cells, Cultured Epithelial Cells / drug effects* Epithelial Cells / metabolism Forkhead Box Protein O3 Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism* Glycoproteins / chemistry Glycoproteins / genetics Glycoproteins / pharmacology* Homeostasis / drug effects Humans Huntingtin Protein Interferon-gamma / pharmacology Mass Spectrometry Metabolome / drug effects* Molecular Sequence Data Mutation Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism Peptides / pharmacology RNA Interference Recombinant Proteins / pharmacology Syndecan-1 / genetics Syndecan-1 / metabolism Tears / chemistry Tears / metabolism Tumor Necrosis Factor-alpha / pharmacology Ubiquitin-Activating Enzymes / genetics Ubiquitin-Activating Enzymes / metabolism Vesicular Transport Proteins / genetics Vesicular Transport Proteins / metabolism
IF 4.106
Times Cited 28
Human and Animal Cells