Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain.
Replication of the complex retrovirus mouse mammary tumor virus (MMTV) is antagonized by murine Apobec3 (mA3), a member of the Apobec family of cytidine deaminases. We have shown that MMTV-encoded Rem protein inhibits proviral mutagenesis by the Apobec enzyme, activation-induced cytidine deaminase (...
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| Format: | Article |
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Public Library of Science (PLoS)
2024-08-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012505 |
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| author | Hyewon Byun Gurvani B Singh Wendy Kaichun Xu Poulami Das Alejandro Reyes Anna Battenhouse Dennis C Wylie Mario L Santiago Mary M Lozano Jaquelin P Dudley |
| author_facet | Hyewon Byun Gurvani B Singh Wendy Kaichun Xu Poulami Das Alejandro Reyes Anna Battenhouse Dennis C Wylie Mario L Santiago Mary M Lozano Jaquelin P Dudley |
| author_sort | Hyewon Byun |
| collection | DOAJ |
| description | Replication of the complex retrovirus mouse mammary tumor virus (MMTV) is antagonized by murine Apobec3 (mA3), a member of the Apobec family of cytidine deaminases. We have shown that MMTV-encoded Rem protein inhibits proviral mutagenesis by the Apobec enzyme, activation-induced cytidine deaminase (AID) during viral replication in BALB/c mice. To further study the role of Rem in vivo, we have infected C57BL/6 (B6) mice with a superantigen-independent lymphomagenic strain of MMTV (TBLV-WT) or a mutant strain that is defective in Rem and its cleavage product Rem-CT (TBLV-SD). Compared to BALB/c, B6 mice were more susceptible to TBLV infection and tumorigenesis. Furthermore, unlike MMTV, TBLV induced T-cell tumors in B6 μMT mice, which lack membrane-bound IgM and conventional B-2 cells. At limiting viral doses, loss of Rem expression in TBLV-SD-infected B6 mice accelerated tumorigenesis compared to TBLV-WT in either wild-type B6 or AID-knockout mice. Unlike BALB/c results, high-throughput sequencing indicated that proviral G-to-A or C-to-T mutations were unchanged regardless of Rem expression in B6 tumors. However, knockout of both AID and mA3 reduced G-to-A mutations. Ex vivo stimulation showed higher levels of mA3 relative to AID in B6 compared to BALB/c splenocytes, and effects of agonists differed in the two strains. RNA-Seq revealed increased transcripts related to growth factor and cytokine signaling in TBLV-SD-induced tumors relative to TBLV-WT-induced tumors, consistent with another Rem function. Thus, Rem-mediated effects on tumorigenesis in B6 mice are independent of Apobec-mediated proviral hypermutation. |
| format | Article |
| id | doaj-art-f6b1a88507fe46f6ac1640c8ffa434a6 |
| institution | Matheson Library |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-f6b1a88507fe46f6ac1640c8ffa434a62025-07-24T05:31:08ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-08-01208e101250510.1371/journal.ppat.1012505Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain.Hyewon ByunGurvani B SinghWendy Kaichun XuPoulami DasAlejandro ReyesAnna BattenhouseDennis C WylieMario L SantiagoMary M LozanoJaquelin P DudleyReplication of the complex retrovirus mouse mammary tumor virus (MMTV) is antagonized by murine Apobec3 (mA3), a member of the Apobec family of cytidine deaminases. We have shown that MMTV-encoded Rem protein inhibits proviral mutagenesis by the Apobec enzyme, activation-induced cytidine deaminase (AID) during viral replication in BALB/c mice. To further study the role of Rem in vivo, we have infected C57BL/6 (B6) mice with a superantigen-independent lymphomagenic strain of MMTV (TBLV-WT) or a mutant strain that is defective in Rem and its cleavage product Rem-CT (TBLV-SD). Compared to BALB/c, B6 mice were more susceptible to TBLV infection and tumorigenesis. Furthermore, unlike MMTV, TBLV induced T-cell tumors in B6 μMT mice, which lack membrane-bound IgM and conventional B-2 cells. At limiting viral doses, loss of Rem expression in TBLV-SD-infected B6 mice accelerated tumorigenesis compared to TBLV-WT in either wild-type B6 or AID-knockout mice. Unlike BALB/c results, high-throughput sequencing indicated that proviral G-to-A or C-to-T mutations were unchanged regardless of Rem expression in B6 tumors. However, knockout of both AID and mA3 reduced G-to-A mutations. Ex vivo stimulation showed higher levels of mA3 relative to AID in B6 compared to BALB/c splenocytes, and effects of agonists differed in the two strains. RNA-Seq revealed increased transcripts related to growth factor and cytokine signaling in TBLV-SD-induced tumors relative to TBLV-WT-induced tumors, consistent with another Rem function. Thus, Rem-mediated effects on tumorigenesis in B6 mice are independent of Apobec-mediated proviral hypermutation.https://doi.org/10.1371/journal.ppat.1012505 |
| spellingShingle | Hyewon Byun Gurvani B Singh Wendy Kaichun Xu Poulami Das Alejandro Reyes Anna Battenhouse Dennis C Wylie Mario L Santiago Mary M Lozano Jaquelin P Dudley Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain. PLoS Pathogens |
| title | Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain. |
| title_full | Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain. |
| title_fullStr | Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain. |
| title_full_unstemmed | Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain. |
| title_short | Apobec-mediated retroviral hypermutation in vivo is dependent on mouse strain. |
| title_sort | apobec mediated retroviral hypermutation in vivo is dependent on mouse strain |
| url | https://doi.org/10.1371/journal.ppat.1012505 |
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