Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response

Abstract

The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses.

Long distance RNA movement

“…In this scenario, PD might serve as an access point (‘hot spot’) for the secretory pathway to circumvent the physical limitations of the cell wall consisting of a narrow cellulose fibre meshwork (Somerville et al ., ). PD pores stretching across the cell wall would be a route enabling cells to exchange secretory vesicles/exosomes analogous to the mammalian extracellular vesicle/exosome signalling system delivering RNA to distant cells (Kouwaki et al ., ; Maas et al ., ). Given the overlap between the proteomes of plant exosome and PD, one could postulate that intercellularly delivered RNAs are transported via the ER‐related membranes spanning the PD pores or as independent vesicles/exosomes via the PD channel.…”

Perception of double‐stranded RNA in plant antiviral immunity

“…During virus infection in animals, dendritic cells and macrophages internalize virus particles and/or extracellular vesicles containing viral RNA. The RNAs are then released into endosomes, where they are recognized by Toll-like receptors to induce immune responses (Baglio et al, 2016;Brencicova and Diebold, 2013;Dreux et al, 2012;Kouwaki et al, 2016Kouwaki et al, , 2017Kouwaki et al, , 2016Kouwaki et al, , 2017Okamoto et al, 2014). In analogy to the mammalian system, it is known that bacterial PAMP receptor-complexes in plants re-localize from the plasma membrane to endosomes (Avila et al, 2015;Beck et al, 2012;Frescatada-Rosa et al, 2015;Russinova et al, 2004) and that plant receptor proteins can signal from endosomes during immunity and development (Geldner et al, 2007;Irani et al, 2012;Mbengue et al, 2016;Sharfman et al, 2011).…”

Unconventional RNA‐binding proteins step into the virus–host battlefront

“…Li & Nagy, 2011;Nagy & Pogany, 2011;R. Y. Wang & Li, 2012) Host mRNA transcription shutoff CPSF4, PABPN1, POLR2 (Herbert & Nag, 2016) Splicing HNRNPA1, HNRNPA2B1, HNRNPA3, HNRNPH, HNRNPC, HNRNPM, U2AF1, U2AF2, SR proteins (Meyer, 2016;Stoltzfus & Madsen, 2006;Tazi et al, 2010) RNA editing/ reading of edited RNA ADAR, ADARB1, ADARB2, RBM15, ALKBH5, YTHDF1, YTHDF3 (Gonzales-van Horn & Sarnow, 2017;Samuel, 2011) Nucleus-cytoplasm shuttling PTBP1, PCBP2, SSB, CSDE1, HNRNPC, HNRNPA1, HNRNPK, HNRNPM, DHX9, SYNCRIP, TIA1, TIAL1, G3BP1 (Lloyd, 2015) vRNA export from nucleus NXF1, ALYREF, RAN, SR proteins, DDX1, DDX3X, DDX5, HNRNPA2B1, SFPQ, MATR3 (Kuss, Mata, Zhang, & Fontoura, 2013;Stake, Bann, Kaddis, & Parent, 2013) vRNA trafficking and packaging HNRNPA2B1, EEF1A1, STAU1 (Cochrane, McNally, & Mouland, 2006;Kaddis Maldonado & Parent, 2016;Stake et al, 2013) Extracellular trafficking HNRNPA2B1, AGO2, SYNCRIP, YBX1 (Kouwaki, Okamoto, Tsukamoto, Fukushima, & Oshiumi, 2017) vRNA stability ELAVL1, PCBP2, HNRNPD, YBX1, ILF3 (Dickson & Wilusz, 2011;Moon & Wilusz, 2013) 5 0 !3 0 RNA degradation XRN1, PATL1, XRN2 (Molleston & Cherry, 2017;Moon, Barnhart, & Wilusz, 2012;Narayanan & Makino, 2013;Oshiumi, Mifsud, et al, 2016;Rigby & Rehwinkel, 2015) 3 0 !5 0 RNA degradation DDX17, ZC3HAV1, UPF1, UPF3, RRP6 (Molleston & Cherry, 2017;Moon, Barnhart, & Wilusz, 2012;Narayanan & Makino, 2013;Oshiumi, Mifsud, et al, 2016;Rigby & Rehwinkel, 2015) Translation PABPC1, EIF4E, EIF4G, EIF4A, EIF2, EIF3, ribosomal proteins, EIF5B, EEF1A1, EEF2, ETF1 (McCormick & Khaperskyy, 2017;Smith & Gray, 2010;Walsh & Mohr, 2011) RNP granules G3BP1, G3BP2, EIF2AK2, LSM14A, XR...…”