Journal Article

Regulator of G-Protein Signaling 19 (RGS19) and Its Partner Gα-Inhibiting Activity Polypeptide 3 (GNAI3) Are Required for zVAD-Induced Autophagy and Cell Death in L929 Cells

Han, Felicia, Huang, Deli, Li, Yuanyue, Zhang, Duan-Wu, Han, Jiahuai, Wu, Ting, Zhang, Ying-Ying

2014

Overview

Autophagy has diverse biological functions and is involved in many biological processes. The L929 cell death induced by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(OMe)-fluoromethyl ketone (zVAD) was shown to be an autophagy-mediated death for which RIP1 and RIP3 were both required. It was also reported that zVAD can induce a small amount of TNF production, which was shown to be required for zVAD-induced L929 cell death, arguing for the contribution of autophagy in the zVAD-induced L929 cell death. In an effort to study RIP3 mediated cell death, we identified regulator of G-protein signaling 19 (RGS19) as a RIP3 interacting protein. We showed that RGS19 and its partner Gα-inhibiting activity polypeptide 3 (GNAI3) are involved in zVAD-, but not TNF-, induced cell death. The role of RGS19 and GNAI3 in zVAD-induced cell death is that they are involved in zVAD-induced autophagy. By the use of small hairpin RNAs and chemical inhibitors, we further demonstrated that zVAD-induced autophagy requires not only RIP1, RIP3, PI3KC3 and Beclin-1, but also RGS19 and GNAI3, and this autophagy is required for zVAD-induced TNF production. Collectively, our data suggest that zVAD-induced L929 cell death is a synergistic result of autophagy, caspase inhibition and autocrine effect of TNF.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Apoptosis / Autocrine signalling / Autophagy / Autophagy - drug effects / Biological activity / Biology / Biology and Life Sciences / Caspase / Cell death / Cell Line, Tumor / Colorectal cancer / Extracellular Signal-Regulated MAP Kinases - metabolism / Gene Knockdown Techniques / GTP-Binding Protein alpha Subunits, Gi-Go - metabolism / Inhibition / JNK Mitogen-Activated Protein Kinases - metabolism / Kinases / Laboratories / Life sciences / MAP Kinase Signaling System - drug effects / Mice / Mortality / Oligopeptides - pharmacology / Phagocytosis / Protein Binding - drug effects / Proteins / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / RGS Proteins - metabolism / Signal transduction / Tumor Necrosis Factor-alpha - biosynthesis / Tumor Necrosis Factor-alpha - pharmacology / Tumor necrosis factor-TNF