An obligatory requirement for the heterotrimeric G protein G i3 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 Gα i class genes, Gα i2 and Gα i3 , demonstrate shared as well as gene-specific functions. The presence of a single active allele of Gα i3 is sufficient for embryonic development, whereas at least one allele of Gα i2 is required for extrauterine life. Mice lacking both Gα i2 and Gα 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 Gα i isoform-specific functions in Gα i2 - and Gα i3 -deficient mice. The subcellular localization of Gα i3 in isolated mouse hepatocytes depends on the cellular metabolic status. Gα 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 Gα i3 are deficient in the inhibitory action of insulin. These data indicate that Gα i3 is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for Gα i3 on autophagosomal membranes.