Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals

Yang, Qian; Zhang, Yao; Zhou, Hui; Deng, Yong-Qiang; Li, Xiaofeng; Miao, Meng; Zhang, Qiang; Zhang, Chao; Hu, Yuanyang; Zhang, Fuchun; Wu, Ligang; Qin, Cheng‐Feng; Xi, Zhenfeng

doi:10.1016/j.immuni.2018.10.003

Cited by 31 publications

(90 citation statements)

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“…Expression of influenza virus NS1, vaccinia virus E3L, reovirus σ3 and Nodamura virus (NoV) B2 proteins inhibits RNAi in plants and/or insect cells (Lichner et al, ; Bucher et al, ; Delgadillo et al, ; Li et al, ). In mammalian cells, a plethora of mammalian virus‐encoded VSRs, including primate foamy virus type 1 (PFV‐1) Tas, NoV B2, HCV core, IAV NS1, HIV Tat, Ebola VP35, VP30 and VP40, CoV N, SARS‐CoV 7a, YFV capsid, DENV NS4B, human enterovirus 71 (HEV 71) 3A and adenovirus virus‐associated RNA I (VA1), can reduce shRNA/siRNA‐mediated knockdown of reporter genes (Table ) (Lu & Cullen, ; Andersson et al, ; Lecellier et al, ; Sullivan & Ganem, ; Wang et al, ; Haasnoot et al, ; Chen et al, ; de Vries et al, ; Karjee et al, ; Fabozzi et al, ; Kakumani et al, ; Cui et al, ; Samuel et al, ; Qiu et al, ). Most viral proteins identified thus far that display VSR activity share the ability to bind dsRNA and mutations that affect their dsRNA‐binding domain block VSR activity, arguing that their principal mode of action is sequestration of dsRNA from Dicer (Table ).…”

Section: Viral Determinants Of Antiviral Rnaimentioning

confidence: 99%

“…Finally, the HEV71‐encoded protein 3A inhibits shRNA‐mediated silencing in mammalian cells, as well as antiviral RNAi in insect cells, and suppresses Dicer‐mediated biogenesis of siRNAs by binding and sequestering long dsRNA in vitro (Qiu et al, ). A point mutation that inactivates 3A's VSR activity reduces viral replication in somatic cells and in suckling mice.…”

Section: Viral Determinants Of Antiviral Rnaimentioning

confidence: 99%

“…A point mutation that inactivates 3A's VSR activity reduces viral replication in somatic cells and in suckling mice. Concomitantly, canonical viRNAs derived from both strands of the 5′terminal region of the HEV71 genome are produced, loaded into RISC and able to silence a reporter bearing complementary sites (Qiu et al, ). Interestingly, the absence of Dicer increases HEV71 accumulation in infected cells despite the presence of an intact IFN pathway, suggesting that, in this case, antiviral RNAi could function irrespective of the IFN system (Qiu et al, ).…”

Section: Viral Determinants Of Antiviral Rnaimentioning

confidence: 99%

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Slicing and dicing viruses: antiviral RNA interference in mammals

et al. 2019

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To protect against the harmful consequences of viral infections, organisms are equipped with sophisticated antiviral mechanisms, including cell‐intrinsic means to restrict viral replication and propagation. Plant and invertebrate cells utilise mostly RNA interference ( RNA i), an RNA ‐based mechanism, for cell‐intrinsic immunity to viruses while vertebrates rely on the protein‐based interferon ( IFN )‐driven innate immune system for the same purpose. The RNA i machinery is conserved in vertebrate cells, yet whether antiviral RNA i is still active in mammals and functionally relevant to mammalian antiviral defence is intensely debated. Here, we discuss cellular and viral factors that impact on antiviral RNA i and the contexts in which this system might be at play in mammalian resistance to viral infection.

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Section: Viral Determinants Of Antiviral Rnaimentioning

confidence: 99%

Section: Viral Determinants Of Antiviral Rnaimentioning

confidence: 99%

Section: Viral Determinants Of Antiviral Rnaimentioning

confidence: 99%

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Slicing and dicing viruses: antiviral RNA interference in mammals

et al. 2019

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“…dmDcr-1 has a degenerate helicase domain and is an ATP-independent enzyme (10), while dmDcr-2, with dedicated antiviral roles (11–13), has a conserved helicase domain that hydrolyzes ATP (14–17). Under certain conditions Homo sapiens Dicer-1 (hsDcr-1) also generates viral siRNAs (18, 19). However, despite conservation of its helicase domain, hsDcr-1 does not hydrolyze ATP in vitro (20), and its helicase domain is not implicated in viral siRNA biogenesis in vivo (19).…”

mentioning

confidence: 99%

Dicer uses distinct modules for recognizing dsRNA termini

Sinha

Iwasa

Shen

et al. 2018

Science

182

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Invertebrates rely on Dicer to cleave viral dsRNA, and Drosophila Dicer-2 distinguishes dsRNA substrates by their termini. Blunt termini promote processive cleavage, while 3’ overhanging termini are cleaved distributively. To understand this discrimination, we used cryo-electron microscopy to solve structures of Drosophila Dicer-2 alone and in complex with blunt dsRNA. While the Platform-PAZ domains have been considered the only Dicer domains that bind dsRNA termini, unexpectedly, we found that the helicase domain is required for binding blunt, but not 3’ overhanging, termini. We further showed that blunt dsRNA is locally unwound and threaded through the helicase domain in an ATP-dependent manner. Our studies reveal a previously unrecognized mechanism for optimizing antiviral defense and set the stage for discovery of helicase-dependent functions in other Dicers.

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“…Cumulative evidences have emerged in support of functional RNAi‐dependent antiviral immunity in mammals (Berkhout, ; Jeang, ; Qiu et al, ). According to this view, the very establishment of infection over cellular defence requires production of extremely potent and efficient VSRs.…”

Section: Discussionmentioning

confidence: 99%

Biphasic regulation of RNA interference during rotavirus infection by modulation of Argonaute2

Mukhopadhyay

Chanda

Patra

et al. 2019

Cellular Microbiology

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RNA interference (RNAi) is an evolutionary ancient innate immune response in plants, nematodes, and arthropods providing natural protection against viral infection. Viruses have also gained counter‐defensive measures by producing virulence determinants called viral‐suppressors‐of‐RNAi (VSRs). Interestingly, in spite of dominance of interferon‐based immunity over RNAi in somatic cells of higher vertebrates, recent reports are accumulating in favour of retention of the antiviral nature of RNAi in mammalian cells. The present study focuses on the modulation of intracellular RNAi during infection with rotavirus (RV), an enteric virus with double‐stranded RNA genome. Intriguingly, a time point‐dependent bimodal regulation of RNAi was observed in RV‐infected cells, where short interfering RNA (siRNA)‐based RNAi was rendered non‐functional during early hours of infection only to be reinstated fully beyond that early infection stage. Subsequent investigations revealed RV nonstructural protein 1 to serve as a putative VSR by associating with and triggering degradation of Argonaute2 (AGO2), the prime effector of siRNA‐mediated RNAi, via ubiquitin–proteasome pathway. The proviral significance of AGO2 degradation was further confirmed when ectopic overexpression of AGO2 significantly reduced RV infection. Cumulatively, the current study presents a unique modulation of host RNAi during RV infection, highlighting the importance of antiviral RNAi in mammalian cells.

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Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals

Cited by 31 publications

References 0 publications

Slicing and dicing viruses: antiviral RNA interference in mammals

Slicing and dicing viruses: antiviral RNA interference in mammals

Dicer uses distinct modules for recognizing dsRNA termini

Biphasic regulation of RNA interference during rotavirus infection by modulation of Argonaute2

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