An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver

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, G αi2 and Gαi3, demonstrate shared as well as gene-specific functions. The presence of a single active allele of G αi3 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 G αi isoform-specific functions in Gαi2- and Gαi3-deficient mice. The subcellular localization of G αi3 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. © 2007 by The National Academy of Sciences of the USA.