The Cap-proximal secondary structures of the 5′UTRs of parainfluenza virus 5 mRNAs specify differential sensitivity to type I interferon and IFIT1

TY - JOUR

T1 - The Cap-proximal secondary structures of the 5′UTRs of parainfluenza virus 5 mRNAs specify differential sensitivity to type I interferon and IFIT1

AU - Hankinson, Jacqueline

AU - Young, Dan

AU - Wignall-Fleming, Elizabeth B.

AU - Lukoszek, Radoslaw

AU - Cowling, Victoria H.

AU - Randall, Richard

AU - Goodbourn, Steve

N1 - Publisher Copyright: © 2025 The Authors.

PY - 2025/3/27

Y1 - 2025/3/27

N2 - Parainfluenza virus 5 (PIV5) is a paramyxovirus that has been isolated from numerous mammalian hosts and is notable for its ability to cause persistent infections. Although PIV5-infected cells are resistant to IFN due to the ability of the V protein to target STAT1 for degradation, PIV5 shows residual IFN sensitivity when infecting cells that have already been exposed to IFN. We have previously reported that the human IFN-stimulated gene with the greatest inhibitory effect on PIV5 is IFIT1. IFIT1 inhibits the translation of incompletely methylated mRNAs (Cap0) but not those 2′-O-methylated at the first transcribed nucleotide (Cap1). All Mononegavirales are thought to generate Cap1 mRNA, so the sensitivity of PIV5 to IFIT1 is surprising. Here, we show that PIV5 generates Cap0 mRNA but not Cap1 mRNA, thus explaining its sensitivity to IFIT1. Furthermore, the sensitivity of different PIV5 genes to IFIT1-mediated translation inhibition varies. In the absence of complete Cap methylation, we show that the presence or absence of 5′-terminal RNA hairpin structures in the 5′UTRs of PIV5 genes determines the extent to which they are sensitive to IFIT1. Notably, the genes involved in RNA synthesis are relatively resistant to IFIT1 inhibition. This presents a potential mechanism by which IFIT1 can regulate the outcome of PIV5 infection in response to IFN and may be important in allowing the virus to establish prolonged/persistent infections.

AB - Parainfluenza virus 5 (PIV5) is a paramyxovirus that has been isolated from numerous mammalian hosts and is notable for its ability to cause persistent infections. Although PIV5-infected cells are resistant to IFN due to the ability of the V protein to target STAT1 for degradation, PIV5 shows residual IFN sensitivity when infecting cells that have already been exposed to IFN. We have previously reported that the human IFN-stimulated gene with the greatest inhibitory effect on PIV5 is IFIT1. IFIT1 inhibits the translation of incompletely methylated mRNAs (Cap0) but not those 2′-O-methylated at the first transcribed nucleotide (Cap1). All Mononegavirales are thought to generate Cap1 mRNA, so the sensitivity of PIV5 to IFIT1 is surprising. Here, we show that PIV5 generates Cap0 mRNA but not Cap1 mRNA, thus explaining its sensitivity to IFIT1. Furthermore, the sensitivity of different PIV5 genes to IFIT1-mediated translation inhibition varies. In the absence of complete Cap methylation, we show that the presence or absence of 5′-terminal RNA hairpin structures in the 5′UTRs of PIV5 genes determines the extent to which they are sensitive to IFIT1. Notably, the genes involved in RNA synthesis are relatively resistant to IFIT1 inhibition. This presents a potential mechanism by which IFIT1 can regulate the outcome of PIV5 infection in response to IFN and may be important in allowing the virus to establish prolonged/persistent infections.

KW - IFIT1

KW - IFN

KW - mRNA Cap structure

KW - parainfluenza virus 5 (PIV5)

UR - https://www.scopus.com/pages/publications/105001272810

U2 - 10.1099/jgv.0.002093

DO - 10.1099/jgv.0.002093

M3 - Article

C2 - 40146622

AN - SCOPUS:105001272810

SN - 0022-1317

VL - 106

JO - Journal of General Virology

JF - Journal of General Virology

IS - 3

M1 - 002093

ER -