Poor induction of interferon-induced 2′,5′-oligoadenylate synthetase (2–5 AS) in cells persistently infected with mumps virus is caused by decrease of STAT-1α

104

An open reading frame (ORF) overlapping the amino-terminal portion of the Sendai virus (SeV)PSendai virus (SeV) is an enveloped virus with a linear, nonsegmented, negative-sense RNA genome of 15,384 nucleotides and belongs to the genus Respirovirus of the family Paramyxoviridae. The genome encodes, in 3Ј-to-5Ј order, the nucleocapsid (N) protein, phospho (P) protein, matrix (M) protein, fusion (F) protein, hemagglutinin-neuraminidase (HA), and large (L) protein. Gene expression is usually monocistronic, generating a single mRNA which primarily directs a single translation product. However, P gene expression is exceptional because it gives rise to multiple protein species by a process known as RNA editing and by the use of an overlapping open reading frame (ORF), as shown in Fig. 1 (for a review, see reference 27).In RNA editing, one nontemplated G residue is cotranscriptionally inserted at a specific position to generate the edited mRNA that encodes the protein termed V (43). The unedited mRNA that is the exact copy of the P gene encodes the P protein, the smaller subunit of RNA polymerase. The P and V proteins are therefore amino coterminal, while the Ϫ1 frame is used to generate the carboxyl-terminal half of the V protein (27). The V unique carboxyl-terminal region contains seven cysteine residues. These cysteine residues are highly conserved in paramyxovirus V proteins, form zinc finger motifs, and indeed bind Zn 2ϩ (17,33). To study the role of SeV V protein, we generated a series of V knockout viruses by reverse genetics and demonstrated that the V protein is completely dispensable for viral replication in tissue culture cells and devotes itself to maintaining high viral loads and causing severe pneumonia in mice (20). This luxury function required for in vivo pathogenesis was mapped to the V unique carboxyl-terminal portion (21) and associated with its zinc binding capacity (17).An ORF overlapping the amino-terminal portion of the SeV P ORF in the ϩ1 frame produces a nested set of carboxycoterminal proteins called CЈ, C, Y1, and Y2 and referred to collectively as the C proteins.

Section: Discussionmentioning

confidence: 99%

Y2, the Smallest of the Sendai Virus C Proteins, Is Fully Capable of both Counteracting the Antiviral Action of Interferons and Inhibiting Viral RNA Synthesis

Kato

Ohnishi

Kohase

et al. 2001

104

“…The V protein of rubulavirus simian virus 5 targets a key factor, signal transducer and activator of transcription 1 (STAT1), on interferon (IFN) signaling for proteasome-mediated degradation, thereby inhibiting IFN signal transduction (1,3,6,7,33,35,48,49). The V proteins of other rubulaviruses, including human parainfluenza virus type 2, mumps virus, and simian virus 41 inhibit IFN signaling likewise by inducing a decrease in the STAT1 or STAT2 level (8,25,30,31,34,35,47,49). In contrast, the respirovirus Sendai virus (SeV), which possesses both V and C ORFs, has evolved functions of the C protein instead of the V protein so as to block IFN signaling (12,18).…”

mentioning

confidence: 99%

The STAT2 Activation Process Is a Crucial Target of Sendai Virus C Protein for the Blockade of Alpha Interferon Signaling

Gotoh

Takeuchi²,

Komatsu³

et al. 2003

All members of the Paramyxovirinae have retained the open reading frame (ORF) for either or both of the accessory proteins, V and C, within the P gene during evolution (26). This finding had suggested crucial roles of the V and C proteins in a virus life cycle, although their roles had remained an enigma for a long time. Several lines of evidence have accumulated, however, demonstrating that the accessory proteins form a group of antagonists against the host immune system (9, 15-17). The Paramyxovirinae family contains three genera: Rubulavirus, Respirovirus, and Morbillivirus. The V protein of rubulavirus simian virus 5 targets a key factor, signal transducer and activator of transcription 1 (STAT1), on interferon (IFN) signaling for proteasome-mediated degradation, thereby inhibiting IFN signal transduction (1,3,6,7,33,35,48,49). The V proteins of other rubulaviruses, including human parainfluenza virus type 2, mumps virus, and simian virus 41 inhibit IFN signaling likewise by inducing a decrease in the STAT1 or STAT2 level (8,25,30,31,34,35,47,49). In contrast, the respirovirus Sendai virus (SeV), which possesses both V and C ORFs, has evolved functions of the C protein instead of the V protein so as to block IFN signaling (12,18). The SeV C ORF produces a nested set of four C proteins, CЈ, C, Y1, and Y2, which are referred to collectively as the C proteins (5, 14). Translation of CЈ, C, Y1, and Y2 initiates at different positions ( 81 ACG, 114 AUG, 183 AUG, and 201 AUG, respectively) and terminates at the same position (UAA 728 ). In addition to the C protein, the shorter forms, Y1 and Y2, have the ability to inhibit IFN signaling (11,22). The C protein, however, does not lead to degradation of any component on the signaling pathway in most cell types (12,18,24,42,49) except for NIH 3T3 mouse embryo fibroblast (MEF) cells (10, 11). The purpose of the present study was to better understand how the SeV C protein inhibits IFN-␣ signaling without degrading cellular proteins on the signaling pathway.The main pathway of IFN-␣/␤ signaling consists of several components, IFN-␣/␤ receptor subunits (IFNAR1 and IF-NAR2), receptor associated kinases (JAK1 and TYK2), two STATs (STAT1 and STAT2), and IFN regulatory factor 9 (p48) (41). Both STAT1 and STAT2 preassociate with the cytoplasmic tail of IFNAR2 in . Binding of IFN-␣/␤ to IFN receptor leads to aggregation of IFNAR1 and IFNAR2, causing the cross-activation of TYK2 and JAK1 (32). TYK2 then phosphorylates IFNAR1 on Tyr 466 (4), which serves as the docking site for the SH2 domain of STAT2 (45). STAT2 binds to the docking site, followed by the phosphorylation of both STAT2 and STAT1. A current model proposed sequential activation of STAT2 and STAT1 in this order (28). The tyrosine-phosphorylated (pY) STAT2-STAT1 heterodimer then translocates into the nucleus and combines IFN regulatory factor 9 (43) to form IFN-stimulated gene factor 3 (ISGF3) and activates transcription of IFN-stimulated genes (ISGs) by binding to IFN-stimulated response elements (ISREs). Two forms o...

“…Subsequently, it was demonstrated that many other paramyxoviruses block IFN signaling (5,8,14,15,25,39,40), although they clearly achieve this goal by distinct molecular mechanisms (40). The V protein of SV5 targets STAT1 for proteasomemediated degradation and is thus responsible for the observed block in IFN signaling (3).…”

mentioning

confidence: 99%

Degradation of STAT1 and STAT2 by the V Proteins of Simian Virus 5 and Human Parainfluenza Virus Type 2, Respectively: Consequences for Virus Replication in the Presence of Alpha/Beta and Gamma Interferons

Andrejeva

Young

Goodbourn

et al. 2002

150

115

Paramyxoviruses, like most other viruses, have evolved specific molecular mechanisms to circumvent certain IFN-induced antiviral responses (for general reviews of how viruses circumvent IFN responses, see references 6 and 18). Paramyxoviruses have nonsegmented, negative-sense, single-stranded RNA genomes. Their genomes are encapsidated within helical nucleocapsids which are surrounded by pleomorphic lipid-containing envelopes through which protrude the virus glycoproteins. A major characteristic used to help classify paramyxoviruses into different subfamilies and genera is the structure of their P genes. In all paramyxoviruses, the P protein, together with the large (L) protein, forms part of the virus RNA polymerase complexes. The P genes of some paramyxoviruses also encode additional proteins. In the genus Rubulavirus, of which simian virus 5 (SV5), mumps virus, and human parainfluenza virus type 2 (hPIV2) are members, the P gene encodes both the P and the V proteins. The P and V proteins have a common N-terminal domain but unique C-terminal domains. In rubulaviruses, the V mRNA is a faithful transcript of the P gene, while the P mRNA transcript has two additional nontemplate G residues (inserted by a specific polymerase stuttering mechanism during transcription of the gene) that alter the reading frame of the mRNA. In viruses belonging to the Respirovirus (e.g., Sendai virus [SeV]) and Morbillivirus (e.g., measles virus)