An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver
- Antje Gohla*,
- Karinna Klement*,
- Roland P. Piekorz*,
- Katja Pexa*,
- Stephan vom Dahl†,‡,
- Karsten Spicher*,§,
- Vladyslav Dreval*,
- Dieter Häussinger†,
- Lutz Birnbaumer¶,‖, and
- Bernd Nürnberg*,**
- *Institut für Biochemie und Molekularbiologie II and
- †Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Klinikum der Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany;
- §Institut für Pharmakologie, Charité-Universitätsmedizin, D-14195 Berlin, Germany; and
- ¶Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709
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Contributed by Lutz Birnbaumer, December 21, 2006 (received for review December 7, 2006)
Abstract
Heterotrimeric G proteins of the Gi class have been implicated in signaling pathways regulating growth and metabolism under physiological and pathophysiological conditions. Knockout mice carrying inactivating mutations in both of the widely expressed Gαi class genes, Gαi2 and Gαi3, demonstrate shared as well as gene-specific functions. The presence of a single active allele of Gαi3 is sufficient for embryonic development, whereas at least one allele of Gαi2 is required for extrauterine life. Mice lacking both Gαi2 and Gαi3 are massively growth-retarded and die in utero. We have used biochemical and cell biological methods together with in situ liver perfusion experiments to study Gαi isoform-specific functions in Gαi2- and Gαi3-deficient mice. The subcellular localization of Gαi3 in isolated mouse hepatocytes depends on the cellular metabolic status. Gαi3 localizes to autophagosomes upon starvation-induced autophagy and distributes to the plasma membrane upon insulin stimulation. Analysis of autophagic proteolysis in perfused mouse livers showed that mice lacking Gαi3 are deficient in the inhibitory action of insulin. These data indicate that Gαi3 is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for Gαi3 on autophagosomal membranes.
Footnotes
- ‖To whom correspondence may be addressed. E-mail: birnbau1{at}niehs.nih.gov
- **To whom correspondence may be addressed at: Institut für Biochemie und Molekularbiologie II, Geb. 22.03.03, Klinikum der Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany . E-mail: bernd.nuernberg{at}uni-duesseldorf.de
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Author contributions: A.G., R.P.P., L.B., and B.N. designed research; K.K., R.P.P., K.P., S.v.D., K.S., and V.D. performed research; S.v.D. and D.H. contributed new reagents/analytic tools; A.G., R.P.P., S.v.D., D.H., L.B., and B.N. analyzed data; and A.G., L.B., and B.N. wrote the paper.
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↵ ‡Present address: St. Franziskus-Hospital, Schönsteinstrasse 63, 50825 Köln, Germany.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0611434104/DC1.
- Abbreviations:
- PTX,
- pertussis toxin;
- MEF,
- mouse embryonic fibroblast;
- wt,
- wild type;
- LC3,
- ubiquitin-like light-chain protein 3.
- © 2007 by The National Academy of Sciences of the USA
