The Heterotrimeric G Protein Gi3 Regulates Hepatic Autophagy Downstream of the Insulin Receptor

Compelling evidence suggests that the heterotrimeric G protein G_i3 specifically transmits the antiautophagic effects of insulin and amino acids in the liver. This points to a previously unrecognized cross talk between the insulin receptor tyrosine kinase and G_i3. Interestingly, G_i3 is localized not only to plasma membranes but also to membranes of the autophagosomal compartment. Furthermore, as part of insulin’s or phenylalanine’s actions to inhibit autophagy, G_i3 is redistributed away from autophagosomes. Therefore, endomembrane-associated rather than plasma membrane-localized G_i3 may serve as the target of insulin’s endocrine and metabolic actions. We therefore propose that the function and regulation of organelle-associated heterotrimeric G proteins may be different from their roles at the plasma membrane where they act as signal transducers of seven-transmembrane receptors. Here, we discuss recent findings and propose a function for G_i3 in mTOR-dependent signaling pathways. We hypothesize that G_i family members may have tissue-specific roles in the regulation of autophagy under different physiological and pathological conditions.

Addendum to:

An Obligatory Requirement for the Heterotrimeric G Protein G_i3 in the Antiautophagic Action of Insulin in the Liver

A. Gohla, K. Klement, R.P. Piekorz, K. Pexa, S. vom Dahl, K. Spicher, V. Dreval, D. Häussinger, L. Birnbaumer and B. Nürnberg

Proc Natl Acad Sci USA 2007; 104:3003-8