Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Thomas Kehrer; Anastasija Cupic; Chengjin Ye; Soner Yildiz; Mehdi Bouhaddou; Nicholas A. Crossland; Erika A. Barrall; Phillip Cohen; Anna Tseng; Tolga Çağatay; Raveen Rathnasinghe; Daniel Flores; Sonia Jangra; Fahmida Alam; Ignacio Mena; Sadaf Aslam; Anjali Saqi; Magdalena Rutkowska; Manisha R. Ummadi; Giuseppe Pisanelli; R. Blake Richardson; Ethan C. Veit; Jacqueline M. Fabius; Margaret Soucheray; Benjamin J. Polacco; Baran Ak; Arturo Marin; Matthew J. Evans; Danielle L. Swaney; Ana S. Gonzalez-Reiche; Emilia M. Sordillo; Harm van Bakel; Viviana Simon; Lorena Zuliani-Alvarez; Beatriz M.A. Fontoura; Brad R. Rosenberg; Nevan J. Krogan; Luis Martinez-Sobrido; Adolfo García-Sastre; Lisa Miorin

doi:10.1016/j.chom.2023.08.003

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Thomas Kehrer, Anastasija Cupic, Chengjin Ye, Soner Yildiz, Mehdi Bouhaddou, Nicholas A. Crossland, Erika A. Barrall, Phillip Cohen, Anna Tseng, Tolga Çağatay, Raveen Rathnasinghe, Daniel Flores, Sonia Jangra, Fahmida Alam, Ignacio Mena, Sadaf Aslam, Anjali Saqi, Magdalena Rutkowska, Manisha R. Ummadi, Giuseppe PisanelliR. Blake Richardson, Ethan C. Veit, Jacqueline M. Fabius, Margaret Soucheray, Benjamin J. Polacco, Baran Ak, Arturo Marin, Matthew J. Evans, Danielle L. Swaney, Ana S. Gonzalez-Reiche, Emilia M. Sordillo, Harm van Bakel, Viviana Simon, Lorena Zuliani-Alvarez, Beatriz M.A. Fontoura, Brad R. Rosenberg, Nevan J. Krogan, Luis Martinez-Sobrido, Adolfo García-Sastre, Lisa Miorin

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Original language	English (US)
Pages (from-to)	1668-1684.e12
Journal	Cell Host and Microbe
Volume	31
Issue number	10
DOIs	https://doi.org/10.1016/j.chom.2023.08.003
State	Published - Oct 11 2023

Keywords

ORF6
Omicron variant
SARS-CoV-2
SARS-CoV-2 pathogenesis
interferon
mRNA export
nuclear import
nucleocytoplasmic trafficking
virus-host interaction

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2023.08.003

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Kehrer, T., Cupic, A., Ye, C., Yildiz, S., Bouhaddou, M., Crossland, N. A., Barrall, E. A., Cohen, P., Tseng, A., Çağatay, T., Rathnasinghe, R., Flores, D., Jangra, S., Alam, F., Mena, I., Aslam, S., Saqi, A., Rutkowska, M., Ummadi, M. R., ... Miorin, L. (2023). Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis. Cell Host and Microbe, 31(10), 1668-1684.e12. https://doi.org/10.1016/j.chom.2023.08.003

Kehrer, T, Cupic, A, Ye, C, Yildiz, S, Bouhaddou, M, Crossland, NA, Barrall, EA, Cohen, P, Tseng, A, Çağatay, T, Rathnasinghe, R, Flores, D, Jangra, S, Alam, F, Mena, I, Aslam, S, Saqi, A, Rutkowska, M, Ummadi, MR, Pisanelli, G, Richardson, RB, Veit, EC, Fabius, JM, Soucheray, M, Polacco, BJ, Ak, B, Marin, A, Evans, MJ, Swaney, DL, Gonzalez-Reiche, AS, Sordillo, EM, van Bakel, H, Simon, V, Zuliani-Alvarez, L, Fontoura, BMA, Rosenberg, BR, Krogan, NJ, Martinez-Sobrido, L, García-Sastre, A & Miorin, L 2023, 'Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis', Cell Host and Microbe, vol. 31, no. 10, pp. 1668-1684.e12. https://doi.org/10.1016/j.chom.2023.08.003

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title = "Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis",

abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.",

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author = "Thomas Kehrer and Anastasija Cupic and Chengjin Ye and Soner Yildiz and Mehdi Bouhaddou and Crossland, {Nicholas A.} and Barrall, {Erika A.} and Phillip Cohen and Anna Tseng and Tolga {\c C}ağatay and Raveen Rathnasinghe and Daniel Flores and Sonia Jangra and Fahmida Alam and Ignacio Mena and Sadaf Aslam and Anjali Saqi and Magdalena Rutkowska and Ummadi, {Manisha R.} and Giuseppe Pisanelli and Richardson, {R. Blake} and Veit, {Ethan C.} and Fabius, {Jacqueline M.} and Margaret Soucheray and Polacco, {Benjamin J.} and Baran Ak and Arturo Marin and Evans, {Matthew J.} and Swaney, {Danielle L.} and Gonzalez-Reiche, {Ana S.} and Sordillo, {Emilia M.} and {van Bakel}, Harm and Viviana Simon and Lorena Zuliani-Alvarez and Fontoura, {Beatriz M.A.} and Rosenberg, {Brad R.} and Krogan, {Nevan J.} and Luis Martinez-Sobrido and Adolfo Garc{\'i}a-Sastre and Lisa Miorin",

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doi = "10.1016/j.chom.2023.08.003",

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AU - Kehrer, Thomas

AU - Cupic, Anastasija

AU - Ye, Chengjin

AU - Yildiz, Soner

AU - Bouhaddou, Mehdi

AU - Crossland, Nicholas A.

AU - Barrall, Erika A.

AU - Cohen, Phillip

AU - Tseng, Anna

AU - Çağatay, Tolga

AU - Rathnasinghe, Raveen

AU - Flores, Daniel

AU - Jangra, Sonia

AU - Alam, Fahmida

AU - Mena, Ignacio

AU - Aslam, Sadaf

AU - Saqi, Anjali

AU - Rutkowska, Magdalena

AU - Ummadi, Manisha R.

AU - Pisanelli, Giuseppe

AU - Richardson, R. Blake

AU - Veit, Ethan C.

AU - Fabius, Jacqueline M.

AU - Soucheray, Margaret

AU - Polacco, Benjamin J.

AU - Ak, Baran

AU - Marin, Arturo

AU - Evans, Matthew J.

AU - Swaney, Danielle L.

AU - Gonzalez-Reiche, Ana S.

AU - Sordillo, Emilia M.

AU - van Bakel, Harm

AU - Simon, Viviana

AU - Zuliani-Alvarez, Lorena

AU - Fontoura, Beatriz M.A.

AU - Rosenberg, Brad R.

AU - Krogan, Nevan J.

AU - Martinez-Sobrido, Luis

AU - García-Sastre, Adolfo

AU - Miorin, Lisa

PY - 2023/10/11

Y1 - 2023/10/11

N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

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KW - interferon

KW - mRNA export

KW - nuclear import

KW - nucleocytoplasmic trafficking

KW - virus-host interaction

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Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Abstract

Keywords

ASJC Scopus subject areas

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