An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver.
Heterotrimeric G proteins of the G(i) 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 Galpha(i) class genes, Galpha(i2) and Galpha(i3), demonstrate shared as well as gene-specific functions. The presence of a single active allele of Galpha(i3) is sufficient for embryonic development, whereas at least one allele of Galpha(i2) is required for extrauterine life. Mice lacking both Galpha(i2) and Galpha(i3) 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 Galpha(i) isoform-specific functions in Galpha(i2)- and Galpha(i3)-deficient mice. The subcellular localization of Galpha(i3) in isolated mouse hepatocytes depends on the cellular metabolic status. Galpha(i3) 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 Galpha(i3) are deficient in the inhibitory action of insulin. These data indicate that Galpha(i3) is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for Galpha(i3) on autophagosomal membranes.
Gohla
Antje
A
Institut für Biochemie und Molekularbiologie II and Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Klinikum der Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany.
Klement
Karinna
K
Piekorz
Roland P
RP
Pexa
Katja
K
vom Dahl
Stephan
S
Spicher
Karsten
K
Dreval
Vladyslav
V
Häussinger
Dieter
D
Birnbaumer
Lutz
L
Nürnberg
Bernd
B
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000276:immunology / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects
D000906:Antibodies; D007328:Insulin; D020033:Protein Isoforms; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse; C417708:Gnai3 protein, mouse; D020962:Heterotrimeric GTP-Binding Proteins