Non-canonical control of Gαi3 by Girdin and Gpsm1 in autophagy
Autophagy represents an essential cellular survival mechanism that eliminates cellular components through lysosome-mediated degradation to maintain cellular and organismic homeostasis1. Impaired autophagy, including dysregulation of autophagy, is a hallmark of many different human diseases such as cancer. Non-canonical G protein signaling plays a critical role in the control of autophagy, but the underlying molecular mechanisms are poorly understood. In this context, Girdin, also called Gα-interacting vesicle-associated protein (GIV), acts as a GEF and plays an important role in the non-canonical control of trimeric G proteins downstream of various classes of receptors, including insulin receptors (INSR). In response to insulin, Girdin activates the AKT/ mTOR axis, which in turn inhibits autophagy. Girdin also influences the localization of the G protein Gαi3 on nascent autophagosomal membranes, where Gαi3 interacts with microtubule- associated proteins 1A/ 1B light chain 3B (LC3) via the GDI Gpsm1 (also known as AGS3). It has been shown that Gαi3 promotes autophagy under starvation conditions, and that insulin signaling activates Girdin to displace Gαi3 from nascent autophagosomes and inhibits autophagy. However, molecular details on how Girdin and Gpsm1 control Gαi3 in the formation of autophagosomes are unclear.
Here, we will decipher the molecular interactions between Girdin and Gpsm1 that control Gαi3 at the onset of autophagy. We aim to define signal inputs that regulate Girdin in control of the Gαi3-Gpsm1-LC3 complex at nascent autophagosomes.