Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain.
Segment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a targe...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1002998&type=printable |
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| _version_ | 1850214272197459968 |
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| author | Helen M Wise Edward C Hutchinson Brett W Jagger Amanda D Stuart Zi H Kang Nicole Robb Louis M Schwartzman John C Kash Ervin Fodor Andrew E Firth Julia R Gog Jeffery K Taubenberger Paul Digard |
| author_facet | Helen M Wise Edward C Hutchinson Brett W Jagger Amanda D Stuart Zi H Kang Nicole Robb Louis M Schwartzman John C Kash Ervin Fodor Andrew E Firth Julia R Gog Jeffery K Taubenberger Paul Digard |
| author_sort | Helen M Wise |
| collection | DOAJ |
| description | Segment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a target for antiviral drugs and vaccination. Surprisingly, M2 is not essential for virus replication in a laboratory setting, although its loss attenuates the virus. To better understand how IAV might replicate without M2, we studied the reversion mechanism of an M2-null virus. Serial passage of a virus lacking the mRNA2 splice donor site identified a single nucleotide pseudoreverting mutation, which restored growth in cell culture and virulence in mice by upregulating mRNA4 synthesis rather than by reinstating mRNA2 production. We show that mRNA4 encodes a novel M2-related protein (designated M42) with an antigenically distinct ectodomain that can functionally replace M2 despite showing clear differences in intracellular localisation, being largely retained in the Golgi compartment. We also show that the expression of two distinct ion channel proteins is not unique to laboratory-adapted viruses but, most notably, was also a feature of the 1983 North American outbreak of H5N2 highly pathogenic avian influenza virus. In identifying a 14th influenza A polypeptide, our data reinforce the unexpectedly high coding capacity of the viral genome and have implications for virus evolution, as well as for understanding the role of M2 in the virus life cycle. |
| format | Article |
| id | doaj-art-3bc38a0a2aa347b38bdcccc4ca32f8e7 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-3bc38a0a2aa347b38bdcccc4ca32f8e72025-08-20T02:08:57ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-01811e100299810.1371/journal.ppat.1002998Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain.Helen M WiseEdward C HutchinsonBrett W JaggerAmanda D StuartZi H KangNicole RobbLouis M SchwartzmanJohn C KashErvin FodorAndrew E FirthJulia R GogJeffery K TaubenbergerPaul DigardSegment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a target for antiviral drugs and vaccination. Surprisingly, M2 is not essential for virus replication in a laboratory setting, although its loss attenuates the virus. To better understand how IAV might replicate without M2, we studied the reversion mechanism of an M2-null virus. Serial passage of a virus lacking the mRNA2 splice donor site identified a single nucleotide pseudoreverting mutation, which restored growth in cell culture and virulence in mice by upregulating mRNA4 synthesis rather than by reinstating mRNA2 production. We show that mRNA4 encodes a novel M2-related protein (designated M42) with an antigenically distinct ectodomain that can functionally replace M2 despite showing clear differences in intracellular localisation, being largely retained in the Golgi compartment. We also show that the expression of two distinct ion channel proteins is not unique to laboratory-adapted viruses but, most notably, was also a feature of the 1983 North American outbreak of H5N2 highly pathogenic avian influenza virus. In identifying a 14th influenza A polypeptide, our data reinforce the unexpectedly high coding capacity of the viral genome and have implications for virus evolution, as well as for understanding the role of M2 in the virus life cycle.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1002998&type=printable |
| spellingShingle | Helen M Wise Edward C Hutchinson Brett W Jagger Amanda D Stuart Zi H Kang Nicole Robb Louis M Schwartzman John C Kash Ervin Fodor Andrew E Firth Julia R Gog Jeffery K Taubenberger Paul Digard Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. PLoS Pathogens |
| title | Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. |
| title_full | Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. |
| title_fullStr | Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. |
| title_full_unstemmed | Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. |
| title_short | Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. |
| title_sort | identification of a novel splice variant form of the influenza a virus m2 ion channel with an antigenically distinct ectodomain |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1002998&type=printable |
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