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Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane.
J Virol. 2007 Sep; 81(18):9812-24.JV

Abstract

The host innate immune response is an important deterrent of severe viral infection in humans and animals. Nuclear import factors function as key gatekeepers that regulate the transport of innate immune regulatory cargo to the nucleus of cells to activate the antiviral response. Using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model, we demonstrate that SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention of import factors at the ER/Golgi membrane leads to a loss of STAT1 transport into the nucleus in response to interferon signaling, thus blocking the expression of STAT1-activated genes that establish an antiviral state. We mapped the region of ORF6, which binds karyopherin alpha 2, to the C terminus of ORF6 and show that mutations in the C terminus no longer bind karyopherin alpha 2 or block the nuclear import of STAT1. We also show that N-terminal deletions of karyopherin alpha 2 that no longer bind to karyopherin beta 1 still retain ORF6 binding activity but no longer block STAT1 nuclear import. Recombinant SARS-CoV lacking ORF6 did not tether karyopherin alpha 2 to the ER/Golgi membrane and allowed the import of the STAT1 complex into the nucleus. We discuss the likely implications of these data on SARS-CoV replication and pathogenesis.

Authors+Show Affiliations

Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, 3304 Hooker Research Center, Chapel Hill, NC 27599-7435, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17596301

Citation

Frieman, Matthew, et al. "Severe Acute Respiratory Syndrome Coronavirus ORF6 Antagonizes STAT1 Function By Sequestering Nuclear Import Factors On the Rough Endoplasmic reticulum/Golgi Membrane." Journal of Virology, vol. 81, no. 18, 2007, pp. 9812-24.
Frieman M, Yount B, Heise M, et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol. 2007;81(18):9812-24.
Frieman, M., Yount, B., Heise, M., Kopecky-Bromberg, S. A., Palese, P., & Baric, R. S. (2007). Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. Journal of Virology, 81(18), 9812-24.
Frieman M, et al. Severe Acute Respiratory Syndrome Coronavirus ORF6 Antagonizes STAT1 Function By Sequestering Nuclear Import Factors On the Rough Endoplasmic reticulum/Golgi Membrane. J Virol. 2007;81(18):9812-24. PubMed PMID: 17596301.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. AU - Frieman,Matthew, AU - Yount,Boyd, AU - Heise,Mark, AU - Kopecky-Bromberg,Sarah A, AU - Palese,Peter, AU - Baric,Ralph S, Y1 - 2007/06/27/ PY - 2007/6/29/pubmed PY - 2007/10/18/medline PY - 2007/6/29/entrez SP - 9812 EP - 24 JF - Journal of virology JO - J Virol VL - 81 IS - 18 N2 - The host innate immune response is an important deterrent of severe viral infection in humans and animals. Nuclear import factors function as key gatekeepers that regulate the transport of innate immune regulatory cargo to the nucleus of cells to activate the antiviral response. Using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model, we demonstrate that SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention of import factors at the ER/Golgi membrane leads to a loss of STAT1 transport into the nucleus in response to interferon signaling, thus blocking the expression of STAT1-activated genes that establish an antiviral state. We mapped the region of ORF6, which binds karyopherin alpha 2, to the C terminus of ORF6 and show that mutations in the C terminus no longer bind karyopherin alpha 2 or block the nuclear import of STAT1. We also show that N-terminal deletions of karyopherin alpha 2 that no longer bind to karyopherin beta 1 still retain ORF6 binding activity but no longer block STAT1 nuclear import. Recombinant SARS-CoV lacking ORF6 did not tether karyopherin alpha 2 to the ER/Golgi membrane and allowed the import of the STAT1 complex into the nucleus. We discuss the likely implications of these data on SARS-CoV replication and pathogenesis. SN - 0022-538X UR - https://www.unboundmedicine.com/medline/citation/17596301/full_citation L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=17596301 DB - PRIME DP - Unbound Medicine ER -