Long Non-Coding RNA BST2/BISPR is Induced by IFN and Regulates the Expression of the Antiviral Factor Tetherin

Abstract

Many long non-coding RNAs (lncRNAs) are expressed in cells but only a few have been well characterized. In these cases, lncRNAs have been shown to be key regulators of several cellular processes. Therefore, there is a great need to understand the function of more lncRNAs and their regulation in response to stimuli. Interferon (IFN) is a key molecule in the cellular antiviral response. IFN binding to its receptor activates transcription of several IFN-stimulated genes (ISGs) that function as potent antivirals. In addition, several ISGs are positive or negative regulators of the IFN pathway. This is essential to ensure a strong antiviral response and a later return of the cell to homeostasis. As the ISGs described to date are coding genes, we sought to determine whether IFN also regulates the expression of long non-coding ISGs. To this aim, we used RNA sequencing to analyze the transcriptome of control and HuH7 cells treated with IFNα2. The results show that IFN-treatment regulates the expression of several unknown non-coding transcripts. We have validated two lncRNAs upregulated after treatment with different doses of type I IFNα2 in different cells or with type III IFNλ. These lncRNAs were also induced by influenza and vesicular stomatitis virus mutants unable to block the IFN response, but not by several wild-type lytic viruses tested. These lncRNA genes were named lncISG15 and lncBST2 as they are located close to ISGs ISG15 and BST2, respectively. Interestingly, inhibition experiments showed that lncBST2 is a positive regulator of BST2. Therefore lncBST2 has been renamed BISPR, from BST2 IFN-stimulated positive regulator. Our results may have therapeutic implications as lncBST2/BISPR, but also lncISG15 and their coding neighbors, are increased in cells infected with hepatitis C virus and in the liver of infected patients. These results allow us to hypothesize that several lncRNAs could be activated by IFN to control the potency of the antiviral IFN response.

The role of BST‐2/Tetherin in host protection and disease manifestation

“…BISPR is expressed from same promoter as BST‐2 but on the opposite direction and its transcription precedes that of BST‐2 174, 175. BISPR and BST‐2 are correlatively upregulated and post‐transcriptional inhibition of BISPR results in reductions in BST‐2 mRNA levels 174.…”

“…BISPR is expressed from same promoter as BST‐2 but on the opposite direction and its transcription precedes that of BST‐2 174, 175. BISPR and BST‐2 are correlatively upregulated and post‐transcriptional inhibition of BISPR results in reductions in BST‐2 mRNA levels 174. Mutant HCV, influenza, and VSV viruses that are able to activate IFN response induce BISPR and BST‐2 in infected cells, suggesting a functional role for BISPR 174.…”

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

“…To date, several lncRNAs have been shown to play an important role in the innate immune response against influenza virus and be associated with viral pathogenesis, including NRAV (negative regulator of antiviral response)[11], NEAT1 (nuclear enriched abundant transcript 1)[30], Bst2/BISPR (bone marrow stromal cell antigen 2 IFN-stimulated positive regulator) [31,32] and VIN (virus inducible lincRNA)[33]. NRAV inhibits the transcription of interferon-stimulated genes via affecting histone modification of these genes (mainly MxA and IFITM3), resulting in the manipulation of the antiviral response[11].…”

“…LncRNA Bst2/BISPR is activated upon infection with the recombinant influenza virus that is deficient in the interferon (IFN) response blocking and after treatment with type I IFN. Bst2/BISPR regulates the expression of genomically neighboring protein-coding gene in an IFN-stimulated gene, cis bone marrow stromal cell antigen 2 (bst2), while the expression of other genes adjacent to bst2 was not affected [31,32]. It is worth noting that the host innate immune response can be regulated by the expression of NRAV, NEAT1 or Bst2/BISPR.…”

“…As far as we known, only a few lncRNAs, such as NRAV (negative regulator of antiviral response)[11], NEAT1 (nuclear enriched abundant transcript 1)[30], Bst2/BISPR (bone marrow stromal cell antigen 2 IFN-stimulated positive regulator) [31,32] and VIN (virus inducible lincRNA) [33] have been demonstrated to be associated with the innate immunity against influenza virus and viral pathogenesis. Therefore, studies are still needed to better understand the potential roles of other lncRNAs in the pathogenesis of influenza virus.…”