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The regulation of type I interferon production by paramyxoviruses - PubMed

Review

The regulation of type I interferon production by paramyxoviruses

Stephen Goodbourn et al. J Interferon Cytokine Res. 2009 Sep.

Abstract

Experimentally, paramyxoviruses are conventionally considered good inducers of type I interferons (IFN-alpha/beta), and have been used as agents in the commercial production of human IFN-alpha. However, in the last few years it has become clear that viruses in general mount a major challenge to the IFN system, and paramyxoviruses are no exception. Indeed, most paramyxoviruses encode mechanisms to inhibit both the production of, and response to, type I IFN. Here we review our knowledge of the type I IFN-inducing signals (by so-called pathogen-associated molecular patterns, or PAMPs) produced during paramyxovirus infections, and discuss how paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMPs by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades.

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Figures

FIG. 1.
FIG. 1.

Classification of paramyxoviruses. The Paramyxoviridae family is divided into Paramyxovirinae and the Pneumovirinae subfamilies. The Paramyxovirinae subfamily contains five genera: respiroviruses, rubulaviruses, henipaviruses, morbilliviruses, and avulaviruses. The Pneumovirinae subfamily contains 2 genera: pneumoviruses and metapneumoviruses. This classification is based predominantly on sequence homology and genome organization. Abbreviations: SeV, Sendai virus; HPIV, human parainfluenza viruses; BPIV3, bovine parainfluenza virus 3; MuV, mumps virus; SV5, simian virus 5; HeV, Hendra virus; NiV, Nipah virus; MeV, measles virus; CDV, canine distemper virus; RPV, rinderpest virus; PDV, phocine distemper virus; NDV, Newcastle disease virus; APMVs, avian paramyxoviruses; HRSV, human respiratory syncytial virus; BRSV, bovine respiratory syncytial virus; HMPV, human metapneumovirus; TRTV, turkey rhinotrachetis virus.

FIG. 2.
FIG. 2.

Organization of the P/V/C genes of Paramyxovirinae and their relationship to their accessory proteins. (A) The P proteins of morbilliviruses, respiroviruses, and henipaviruses are translated from mRNAs produced as faithful copies of their P/V/C genes (green bar). Insertion of a single G at the RNA-editing site generates a transcript that encodes the V protein, and insertion of 2 G residues generates a transcript that encodes the W proteins and D proteins (HPIV3). The P, V, W, and D proteins share a common N-terminus (blue bar), but distinct C-termini (P = pink bar, V = light green bar, W and D = yellow bar). The C protein(s) (lilac bars) are generated by translation of the P/V/W/D mRNAs using alternative initiation codons. Translation of the prototypical C protein begins at an AUG that resides downstream of P protein initiation codon, and the Y1 and Y2 proteins of Sendai virus are translated from AUGs that reside even further downstream. The C′ protein made by Sendai virus is translated from an ACG codon that resides 5′ to the AUG of the P protein. (B) The P proteins of avulaviruses are also translated from mRNAs produced as faithful copies of their P/V genes (green bar). Insertion of a single G at the RNA-editing site generates a transcript that encodes the V protein, and insertion of 2 G residues generates a transcript that encodes the I protein. (C) In contrast, the V proteins of rubulaviruses are translated from mRNAs produced as faithful copies of their P/V genes (green bar). Insertion of 1 or 4 G residues at the RNA-editing site generates a transcript that encodes the I protein, and insertion of 2 G residues generates a transcript that encodes the P protein.

FIG. 3.
FIG. 3.

Paramyxovirus accessory proteins target the intracellular viral pathogen-associated molecular patterns (PAMP) signaling pathways. The signaling pathways leading from the RNA helicases mda-5 and RIG-I to IFN-β induction are shown (reviewed in Randall and Goodbourn (2008), Gale and Sen (2009)). As discussed in the text, paramyxovirus V proteins interact with mda-5 and prevent its activation. Sendai virus (SeV) C protein targets RIG-I, although a specific molecular interaction has yet to be shown. The NS2 protein of human respiratory syncytial virus (HRSV) directly binds to RIG-I and inhibits its activity. The V proteins of human parainfluenza virus 2 (HPIV2), simian virus 5 (PIV5, formerly SV5), and mumps virus (MuV) interact with and inhibit TBK1 and IKK-ɛ, and NiV V inhibits IKK-ɛ (although not TBK1). The C protein of rinderpest virus (RPV) and the W protein of Nipah virus (NiV) have uncharacterized nuclear targets that act downstream of transcription factors.

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