tetano
Editor, Senior Moderator
Cell Host Microbe
. 2023 Sep 20;S1931-3128(23)00328-1.
doi: 10.1016/j.chom.2023.08.003. Online ahead of print. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis
Thomas Kehrer[SUP] 1 [/SUP], Anastasija Cupic[SUP] 1 [/SUP], Chengjin Ye[SUP] 2 [/SUP], Soner Yildiz[SUP] 3 [/SUP], Mehdi Bouhaddou[SUP] 4 [/SUP], Nicholas A Crossland[SUP] 5 [/SUP], Erika A Barrall[SUP] 1 [/SUP], Phillip Cohen[SUP] 1 [/SUP], Anna Tseng[SUP] 5 [/SUP], Tolga Çağatay[SUP] 6 [/SUP], Raveen Rathnasinghe[SUP] 7 [/SUP], Daniel Flores[SUP] 3 [/SUP], Sonia Jangra[SUP] 3 [/SUP], Fahmida Alam[SUP] 3 [/SUP], Ignacio Mena[SUP] 3 [/SUP], Sadaf Aslam[SUP] 3 [/SUP], Anjali Saqi[SUP] 8 [/SUP], Magdalena Rutkowska[SUP] 1 [/SUP], Manisha R Ummadi[SUP] 9 [/SUP], Giuseppe Pisanelli[SUP] 10 [/SUP], R Blake Richardson[SUP] 11 [/SUP], Ethan C Veit[SUP] 1 [/SUP], Jacqueline M Fabius[SUP] 12 [/SUP], Margaret Soucheray[SUP] 9 [/SUP], Benjamin J Polacco[SUP] 9 [/SUP], Baran Ak[SUP] 11 [/SUP], Arturo Marin[SUP] 3 [/SUP], Matthew J Evans[SUP] 11 [/SUP], Danielle L Swaney[SUP] 9 [/SUP], Ana S Gonzalez-Reiche[SUP] 13 [/SUP], Emilia M Sordillo[SUP] 14 [/SUP], Harm van Bakel[SUP] 15 [/SUP], Viviana Simon[SUP] 16 [/SUP], Lorena Zuliani-Alvarez[SUP] 9 [/SUP], Beatriz M A Fontoura[SUP] 6 [/SUP], Brad R Rosenberg[SUP] 11 [/SUP], Nevan J Krogan[SUP] 9 [/SUP], Luis Martinez-Sobrido[SUP] 2 [/SUP], Adolfo García-Sastre[SUP] 17 [/SUP], Lisa Miorin[SUP] 18 [/SUP]
Affiliations
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
61L 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.
Keywords: ORF6; Omicron variant; SARS-CoV-2; SARS-CoV-2 pathogenesis; interferon; mRNA export; nuclear import; nucleocytoplasmic trafficking; virus-host interaction.
. 2023 Sep 20;S1931-3128(23)00328-1.
doi: 10.1016/j.chom.2023.08.003. Online ahead of print. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis
Thomas Kehrer[SUP] 1 [/SUP], Anastasija Cupic[SUP] 1 [/SUP], Chengjin Ye[SUP] 2 [/SUP], Soner Yildiz[SUP] 3 [/SUP], Mehdi Bouhaddou[SUP] 4 [/SUP], Nicholas A Crossland[SUP] 5 [/SUP], Erika A Barrall[SUP] 1 [/SUP], Phillip Cohen[SUP] 1 [/SUP], Anna Tseng[SUP] 5 [/SUP], Tolga Çağatay[SUP] 6 [/SUP], Raveen Rathnasinghe[SUP] 7 [/SUP], Daniel Flores[SUP] 3 [/SUP], Sonia Jangra[SUP] 3 [/SUP], Fahmida Alam[SUP] 3 [/SUP], Ignacio Mena[SUP] 3 [/SUP], Sadaf Aslam[SUP] 3 [/SUP], Anjali Saqi[SUP] 8 [/SUP], Magdalena Rutkowska[SUP] 1 [/SUP], Manisha R Ummadi[SUP] 9 [/SUP], Giuseppe Pisanelli[SUP] 10 [/SUP], R Blake Richardson[SUP] 11 [/SUP], Ethan C Veit[SUP] 1 [/SUP], Jacqueline M Fabius[SUP] 12 [/SUP], Margaret Soucheray[SUP] 9 [/SUP], Benjamin J Polacco[SUP] 9 [/SUP], Baran Ak[SUP] 11 [/SUP], Arturo Marin[SUP] 3 [/SUP], Matthew J Evans[SUP] 11 [/SUP], Danielle L Swaney[SUP] 9 [/SUP], Ana S Gonzalez-Reiche[SUP] 13 [/SUP], Emilia M Sordillo[SUP] 14 [/SUP], Harm van Bakel[SUP] 15 [/SUP], Viviana Simon[SUP] 16 [/SUP], Lorena Zuliani-Alvarez[SUP] 9 [/SUP], Beatriz M A Fontoura[SUP] 6 [/SUP], Brad R Rosenberg[SUP] 11 [/SUP], Nevan J Krogan[SUP] 9 [/SUP], Luis Martinez-Sobrido[SUP] 2 [/SUP], Adolfo García-Sastre[SUP] 17 [/SUP], Lisa Miorin[SUP] 18 [/SUP]
Affiliations
- PMID: 37738983
- DOI: 10.1016/j.chom.2023.08.003
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
61L 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.Keywords: ORF6; Omicron variant; SARS-CoV-2; SARS-CoV-2 pathogenesis; interferon; mRNA export; nuclear import; nucleocytoplasmic trafficking; virus-host interaction.