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

• Published in: PloS one Vol. 9; no. 4; p. e94634
• Main Authors: Wu, Ting, Li, Yuanyue, Huang, Deli, Han, Felicia, Zhang, Ying-Ying, Zhang, Duan-Wu, Han, Jiahuai
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.04.2014; Public Library of Science (PLoS)
• Subjects: 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; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094634

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.