Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection.
While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very lit...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-07-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012170 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846091519234146304 |
|---|---|
| author | Ranran Wang Taylor E Senay Tiana T Luo Wei Liu James M Regan Nicholas J H Salisbury Denise A Galloway Jianxin You |
| author_facet | Ranran Wang Taylor E Senay Tiana T Luo Wei Liu James M Regan Nicholas J H Salisbury Denise A Galloway Jianxin You |
| author_sort | Ranran Wang |
| collection | DOAJ |
| description | While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy. |
| format | Article |
| id | doaj-art-90da2940d66a4e6691ecc6d3a55396a9 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-90da2940d66a4e6691ecc6d3a55396a92025-01-10T05:31:49ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-07-01207e101217010.1371/journal.ppat.1012170Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection.Ranran WangTaylor E SenayTiana T LuoWei LiuJames M ReganNicholas J H SalisburyDenise A GallowayJianxin YouWhile Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.https://doi.org/10.1371/journal.ppat.1012170 |
| spellingShingle | Ranran Wang Taylor E Senay Tiana T Luo Wei Liu James M Regan Nicholas J H Salisbury Denise A Galloway Jianxin You Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection. PLoS Pathogens |
| title | Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection. |
| title_full | Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection. |
| title_fullStr | Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection. |
| title_full_unstemmed | Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection. |
| title_short | Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection. |
| title_sort | merkel cell polyomavirus protein alto modulates tbk1 activity to support persistent infection |
| url | https://doi.org/10.1371/journal.ppat.1012170 |
| work_keys_str_mv | AT ranranwang merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT tayloresenay merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT tianatluo merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT weiliu merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT jamesmregan merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT nicholasjhsalisbury merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT deniseagalloway merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection AT jianxinyou merkelcellpolyomavirusproteinaltomodulatestbk1activitytosupportpersistentinfection |