Keratins regulate protein biosynthesis through localization of GLUT1 and -3 upstream of AMP kinase and Raptor.
Keratin intermediate filament proteins form cytoskeletal scaffolds in epithelia, the disruption of which affects cytoarchitecture, cell growth, survival, and organelle transport. However, owing to redundancy, the global function of keratins has not been defined in full. Using a targeted gene deletion strategy, we generated transgenic mice lacking the entire keratin multiprotein family. In this study, we report that without keratins, embryonic epithelia suffer no cytolysis and maintain apical polarity but display mislocalized desmosomes. All keratin-null embryos die from severe growth retardation at embryonic day 9.5. We find that GLUT1 and -3 are mislocalized from the apical plasma membrane in embryonic epithelia, which subsequently activates the energy sensor adenosine monophosphate kinase (AMPK). Analysis of the mammalian target of rapamycin (mTOR) pathway reveals that AMPK induction activates Raptor, repressing protein biosynthesis through mTORC1's downstream targets S6 kinase and 4E-binding protein 1. Our findings demonstrate a novel keratin function upstream of mTOR signaling via GLUT localization and have implications for pathomechanisms and therapy approaches for keratin disorders and the analysis of other gene families.
Vijayaraj
Preethi
P
Abteilung für Zellbiochemie, Institut für Biochemie und Molekularbiologie and 2 Bonner Forum Biomedizin, Universität Bonn, 53115 Bonn, Germany.
Kröger
Cornelia
C
Reuter
Ursula
U
Windoffer
Reinhard
R
Leube
Rudolf E
RE
Magin
Thomas M
TM
D048868:Adaptor Proteins, Signal Transducing; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D053531:Keratins, Type II / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D053531:Keratins, Type II; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse; D000263:Adenylate Kinase