An Inhibitory Role of the G-Protein Regulator AGS3 in mTOR-Dependent Macroautophagy

Abstract

Macroautophagy is a cellular process whereby the cell sequesters and recycles cytosolic constituents in a lysosome-dependent manner. It has also been implicated in a number of disorders, including cancer and neurodegeneration. Although a previous report that AGS3 over-expression promotes macroautophagy suggests a stimulatory role of AGS3 in this process, we have found that knock-down of AGS3, unexpectedly, also induces macroautophagy, indicating an inhibitory function of endogenous AGS3 in macroautophagy. Interestingly, AGS3 phosphorylation is decreased upon induction of mammalian target of rapamycin (mTOR)-dependent macroautophagy. Moreover, unlike wild-type AGS3, over-expression of an AGS3 mutant lacking this modification fails to enhance macroautophagic activity. These observations imply that AGS3 phosphorylation may participate in the modulation of macroautophagy.

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…1). In mammalian systems, AGS3 is implicated in asymmetric cell division, neuronal plasticity and addiction, autophagy, membrane protein trafficking, polycystic kidney disease, renal response to ischemia, immune cell chemotaxis, insulin-like growth factor-1 mediated ciliary resorption, cardiovascular regulation, and metabolism (Blumer et al, 2002(Blumer et al, , 2006(Blumer et al, , 2008Ghosh et al, 2003;Gotta et al, 2003;Pattingre et al, 2003;Bowers et al, 2004Bowers et al, , 2008Sato et al, 2004;Yao et al, 2005Yao et al, , 2006Groves et al, 2007;Willard et al, 2008;Groves et al, 2010;Nadella et al, 2010;Vural et al, 2010;Hofler and Koelle, 2011;Regner et al, 2011;Chauhan et al, 2012;Kwon et al, 2012;Conley and Watts, 2013;Kamakura et al, 2013;Yeh et al, 2013). AGS3 single nucleotide polymorphisms are associated with diabetes and glucose handling (Scott et al, 2012;Hara et al, 2014;Huyghe et al, 2013).…”

“…2A), function as part of a distinct signaling pathway (e.g., GaGPR signaling module) (Fig. 2B), serve as a chaperone for Ga, and/or impact basic cellular events such as autophagy (Pattingre et al, 2003;Groves et al, 2010;Vural et al, 2010;Garcia-Marcos et al, 2011a) and secretory pathway dynamics (Groves et al, 2007;Oner et al, 2013b).…”

Translocation of Activator of G-protein Signaling 3 to the Golgi Apparatus in Response to Receptor Activation and Its Effect on the trans-Golgi Network

“…ity, autophagy, protein trafficking, hearing, morphogenesis, and the renal response to injury (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Although the majority of G␣ within the cell probably exists as part of the G␣␤␥ heterotrimer at the cell cortex, a subpopulation of G␣ i is apparently complexed with GPR proteins.…”

Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy

“…Activating G-protein Signaling 3 (AGS3) protein is highly expressed in the brain and contributes to cardiac and metabolic functions. 25) Interestingly, both the overexpression and down-regulation of AGS3 induces autophagy, 26) confirming the necessity of fine-tuning in autophagy when developing therapeutic strategies.…”