Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Abstract

The retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs.Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I-and MDA-5-initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-x L rescued nonmalignant, but not melanoma, cells from RIG-I-and MDA-5-mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-x L , results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis.

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

“…The downstream signaling of pIC has been extensively studied. pIC typically leads to an activation of receptors recognizing ss-and dsRNA such as the endosomal receptor TLR3 and the cytosolic helicases melanoma differentiation-associated protein 5 (MDA-5) and retinoic acid inducible gene I (RIG-I) (25)(26)(27). McAllister et al (27) reported that i.p.…”

Mouse Embryonic Stem Cells Have Underdeveloped Antiviral Mechanisms That Can Be Exploited for the Development of mRNA-Mediated Gene Expression Strategy

“…RIG-I is the major receptor that mediates the effects of viral ssRNA and synthetic ssRNA, especially those with a 3p-group [16,17,41,42,47]. In addition to its well-defined function in inducing type I IFN, a recent study showed that RIG-I activation leads to apoptosis by a mechanism that is independent of IFN expression in SKOV3 cells [48]. Therefore, the RIG-I pathway may play a major role in mediating the IFNb expression and cytotoxicity induced by ssRNA, as demonstrated in 10T1/2 cells where 3p-80nt-ssRNA induced IFNb expression and cell death within a similar time course.…”

Hitting the right button: MAVS-mediated defense against HAV infection

“…In search of the mechanism mediating MAVS-induced death, the authors found that HAV-induced death of infected hepatocytes depends on the transcription factors IRF3 and IRF7. Since HAVinduced liver damage is independent of IFNAR signaling, IRF3/7 may trigger death directly through its transcriptional activity on pro-apoptotic molecules like the BH3-only protein PMAIP1 [5] or in a transcription-independent fashion by interacting with mitochondrial Bax [6]. Hirai-Yuki et al provide compelling evidence in their study for the key role of MAVS in the control of hepatocyte infection with an RNA virus like HAV.…”