Nonsense‐mediated mRNA decay does not restrict influenza A virus propagation

Abstract

Nonsense-mediated mRNA decay (NMD) was identified as a process to degrade flawed cellular messenger RNA (mRNA). Within the last decades it was also shown that NMD carries virus-restricting capacities and thus could be considered a part of the cellular antiviral system. As this was shown to affect primarily positive-sense single stranded RNA ((+)ssRNA) viruses there is only scarce knowledge if this also applies to negative-sense single stranded RNA ((−)ssRNA) viruses. Influenza A viruses (IAVs) harbour a segmented (−)ssRNA genome. During their replication IAVs produce numerous RNA transcripts and simultaneously impair cellular transcription and translation. The viral mRNAs hold several molecular patterns which can elicit NMD and in turn would lead to their degradation. This, in consequence, may mitigate viral propagation. Thus, we examined if a knockdown or a pharmacological inhibition of NMD key components may influence IAV replication. Additionally, we performed similar experiments with respiratory syncytial virus (RSV), another (−)ssRNA virus, but with a non-segmented genome. Although it seemed that a knockdown of up-frameshift protein 1 (UPF1), the central NMD factor, slightly increased viral mRNA and protein levels, no significant alteration of viral replication could be observed, implying that the NMD machinery may not have restricting capacities against (−)ssRNA viruses.

Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

“…A uORF is present in 4/7 EBOV mRNAs (Shabman et al, 2013), presumably qualifying them as NMD substrates. However, our results revealed that UPF1 and GSPT1 exerted only a brief restriction of EBOV infection at the onset of viral infection, similar to that seen for influenza virus infection (Tran et al, 2021). At later times of infection, neither UPF1 nor GSPT1-depletion enhanced EBOV multiplication in human hepatocytes.…”

“…Here we discovered two critical players in the cellular nonsense-mediated decay (NMD) pathway, UPF1 and GSPT1, which can both regulate EBOV infection. Although the role of NMD decay in virus infection has been examined for positive-strand and double-strand RNA viruses, retroviruses and influenza (Balistreri et al, 2017;Declercq et al, 2020;Popp et al, 2020;Tran et al, 2021), how NMD affects negative-strand RNA viruses like EBOV that replicate in the cytoplasm remains unclear. In the cellular NMD pathway, UPF1 degrades aberrant mRNAs by binding to the translation-termination complex (GSPT1/eRF3-eRF1) upon ribosomal recognition of a premature termination codon (PTC) in the mRNA (Kurosaki and Maquat, 2016).…”

“…This process is typically coupled with translation termination and promoted by the interaction between UPF1 and the termination complex (GSPT1/eRF3-eRF1) (Kurosaki et al, 2019). The NMD pathway has been shown to restrict multiple positive- and double-strand RNA viruses, but not retroviruses or influenza virus (Ajamian et al, 2008b; Balistreri et al, 2017; Declercq et al, 2020; Popp et al, 2020; Tran et al, 2021). How NMD affects negative-strand RNA viruses like EBOV that replicate in the cytoplasm remains to be determined.…”

Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

“…This process is typically coupled with translation termination and promoted by the interaction between UPF1 and the termination complex (GSPT1/eRF3-eRF1) ( Kurosaki et al, 2019 ). The NMD pathway has been shown to restrict multiple positive- and double-stranded RNA viruses but not retroviruses or influenza virus ( Ajamian et al, 2008 ; Balistreri et al, 2017 ; Declercq et al, 2020 ; Popp et al, 2020 ; Tran et al, 2021 ). How NMD affects negative-strand RNA viruses like EBOV that replicate in the cytoplasm remains to be determined.…”

Development of rapid nucleic acid testing techniques for common respiratory infectious diseases in the Chinese population

“…FluA is a negative-sense single-stranded RNA virus. Genome sequencing is approximately 13 kb in length ( Lee, 2020 ; Tran et al, 2021 ). Currently, conventional PCR and RT-PCR are mainly used for the detection of upper respiratory tract infections caused by the influenza A subtype H1N1 virus.…”