Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein
Abstract Nucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, a...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03303-1 |
| _version_ | 1818725645067223040 |
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| author | Wen Meng Shou-Jiang Gao |
| author_facet | Wen Meng Shou-Jiang Gao |
| author_sort | Wen Meng |
| collection | DOAJ |
| description | Abstract Nucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, and some mRNAs. In this study, we have identified an essential role of XPO1 in regulating Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication during primary infection of primary human umbilical vein endothelial cells. Treatment with an XPO1 inhibitor KPT-8602 and short hairpin RNA (shRNA)-mediated knockdown of XPO1 reduced KSHV lytic replication but had no effect on KSHV entry and trafficking. XPO1 inhibition induced retention of autophagy adaptor protein p62 (SQSTM1) in the nucleus, which enhanced activation of TBK1 and IRF3. As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection. |
| first_indexed | 2024-12-17T21:45:36Z |
| format | Article |
| id | doaj.art-48b3088efcb3426785d7cf1461047610 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-17T21:45:36Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-48b3088efcb3426785d7cf14610476102022-12-21T21:31:28ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111610.1038/s41419-020-03303-1Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor proteinWen Meng0Shou-Jiang Gao1UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of PittsburghUPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of PittsburghAbstract Nucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, and some mRNAs. In this study, we have identified an essential role of XPO1 in regulating Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication during primary infection of primary human umbilical vein endothelial cells. Treatment with an XPO1 inhibitor KPT-8602 and short hairpin RNA (shRNA)-mediated knockdown of XPO1 reduced KSHV lytic replication but had no effect on KSHV entry and trafficking. XPO1 inhibition induced retention of autophagy adaptor protein p62 (SQSTM1) in the nucleus, which enhanced activation of TBK1 and IRF3. As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection.https://doi.org/10.1038/s41419-020-03303-1 |
| spellingShingle | Wen Meng Shou-Jiang Gao Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein Cell Death and Disease |
| title | Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein |
| title_full | Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein |
| title_fullStr | Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein |
| title_full_unstemmed | Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein |
| title_short | Targeting XPO1 enhances innate immune response and inhibits KSHV lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein |
| title_sort | targeting xpo1 enhances innate immune response and inhibits kshv lytic replication during primary infection by nuclear stabilization of the p62 autophagy adaptor protein |
| url | https://doi.org/10.1038/s41419-020-03303-1 |
| work_keys_str_mv | AT wenmeng targetingxpo1enhancesinnateimmuneresponseandinhibitskshvlyticreplicationduringprimaryinfectionbynuclearstabilizationofthep62autophagyadaptorprotein AT shoujianggao targetingxpo1enhancesinnateimmuneresponseandinhibitskshvlyticreplicationduringprimaryinfectionbynuclearstabilizationofthep62autophagyadaptorprotein |