Mammals II
processing of 5’ termini of RNAs produced by phage polymerases when such RNAs are used in mammalian cells. It is not clear how PKR and RIG-I pathways are integrated. RIG-I binds siRNAs (with or without 2-nt 3’ overhangs) in vitro and it shows greater unwinding of blunt-ended siRNAs. Unwinding is then translated into the interferon activation mediated via IRF-3. Toll-like Receptor 3 (TLR3) TLR3 is a member of the Toll-like receptor (TLR) family and functions as a sensor of extracellular, intracellular and viral dsRNAs (Amarante et al., 2011; Seo et al., 2013; Wang et al., 2015b; Wu et al., 2015b; Yang et al., 2006b). TLR3 has distinct or complementary roles to RIG-I and related helicases in sensing foreign molecules and activating downstream responses (Livengood et al., 2007; McCartney et al., 2009; Slater et al., 2010; Wu et al., 2015b). Oligoadenylate Synthetase (OAS) Interferon and dsRNA also activate 2’,5’-oligoadenylate synthetase (2’,5’-OAS) that produces 2’,5’ oligoadenylates with 5’-terminal triphosphate residues that subsequently induce activation of RNAse L; a protein responsible for general RNA degradation (de Veer et al., 2005). TARBP2 and PACT Interactions between RNAi, miRNA, and interferon response are poorly understood. There are two clear mechanistic connections between these two pathways. First, TARBP2 and PACT, two dsRNA binding proteins, which were mentioned earlier as Dicer-interacting proteins, interact also with PKR. Notably, while TARBP2 inhibits PKR (Cosentino et al., 1995; Park et al., 1994), PACT has the opposite role (Patel and Sen, 1998). While cytoplasmic long dsRNA in somatic cells apparently triggers the interferon response, it is not clear if the same dsRNA is also routed into the RNAi pathways. Experiments in oocytes and undifferentiated embryonic stem cells (Stein et al., 2005; Yang et al., 2001) suggest that RNAi dominates response to cytoplasmic long dsRNA in the absence of a strong interferon response and that the interferon pathway dominates when its relevant components are present. On the other hand, this view may be too simplistic as it does not explain the lack of both, RNAi and interferon response, in somatic cells expressing long dsRNA (Nejepinska et al., 2012; Nejepinska et al., 2014). In any case, understanding the role of TARBP2 and PACT isoforms in routing long dsRNA into RNAi and interferon pathways requires further studies. There is a clear evolutionary connection between RNAi and interferon response. The above-mentioned mammalian RNA helicases RIG-I, LGP2 and MDA5 are the closest homologs of helicases involved in processing of long dsRNA during RNAi in C. elegans. Notably, RIG-I is an established component of the interferon response to long dsRNA (Yoneyama et al., 2004). This suggests that the interferon response, which has a common
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09.07.20 8:34 Ukázka elektronické knihy, UID: KOS279588