c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity
Abstract During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find t...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42765-7 |
| _version_ | 1797636798008000512 |
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| author | Asif A. Dar Dale D. Kim Scott M. Gordon Kathleen Klinzing Siera Rosen Ipsita Guha Nadia Porter Yohaniz Ortega Katherine S. Forsyth Jennifer Roof Hossein Fazelinia Lynn A. Spruce Laurence C. Eisenlohr Edward M. Behrens Paula M. Oliver |
| author_facet | Asif A. Dar Dale D. Kim Scott M. Gordon Kathleen Klinzing Siera Rosen Ipsita Guha Nadia Porter Yohaniz Ortega Katherine S. Forsyth Jennifer Roof Hossein Fazelinia Lynn A. Spruce Laurence C. Eisenlohr Edward M. Behrens Paula M. Oliver |
| author_sort | Asif A. Dar |
| collection | DOAJ |
| description | Abstract During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses. |
| first_indexed | 2024-03-11T12:39:19Z |
| format | Article |
| id | doaj.art-13ee6ca256cb4b35a160900e56452abc |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T12:39:19Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-13ee6ca256cb4b35a160900e56452abc2023-11-05T12:22:21ZengNature PortfolioNature Communications2041-17232023-11-0114112110.1038/s41467-023-42765-7c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunityAsif A. Dar0Dale D. Kim1Scott M. Gordon2Kathleen Klinzing3Siera Rosen4Ipsita Guha5Nadia Porter6Yohaniz Ortega7Katherine S. Forsyth8Jennifer Roof9Hossein Fazelinia10Lynn A. Spruce11Laurence C. Eisenlohr12Edward M. Behrens13Paula M. Oliver14Division of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Neonatology, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Cell Pathology, The Children’s Hospital of PhiladelphiaDivision of Cell Pathology, The Children’s Hospital of PhiladelphiaDivision of Cell Pathology, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaDivision of Rheumatology, The Children’s Hospital of PhiladelphiaDivision of Protective Immunity, The Children’s Hospital of PhiladelphiaAbstract During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.https://doi.org/10.1038/s41467-023-42765-7 |
| spellingShingle | Asif A. Dar Dale D. Kim Scott M. Gordon Kathleen Klinzing Siera Rosen Ipsita Guha Nadia Porter Yohaniz Ortega Katherine S. Forsyth Jennifer Roof Hossein Fazelinia Lynn A. Spruce Laurence C. Eisenlohr Edward M. Behrens Paula M. Oliver c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity Nature Communications |
| title | c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity |
| title_full | c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity |
| title_fullStr | c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity |
| title_full_unstemmed | c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity |
| title_short | c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity |
| title_sort | c myc uses cul4b to preserve genome integrity and promote antiviral cd8 t cell immunity |
| url | https://doi.org/10.1038/s41467-023-42765-7 |
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