The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication
ABSTRACT Peste des petits ruminants virus (PPRV) is an important pathogen that has long been a significant threat to small ruminant productivity worldwide. Iron metabolism is vital to the host and the pathogen. However, the mechanism underlying host-PPRV interactions from the perspective of iron met...
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American Society for Microbiology
2025-04-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00127-25 |
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| author | Bo Wen Wenchi Chang Lulu Yang Daiyue Lv Lizhen Wang Lei Wang Yanzhao Xu Jianhe Hu Ke Ding Qinghong Xue Xuefeng Qi Bo Yang Jingyu Wang |
| author_facet | Bo Wen Wenchi Chang Lulu Yang Daiyue Lv Lizhen Wang Lei Wang Yanzhao Xu Jianhe Hu Ke Ding Qinghong Xue Xuefeng Qi Bo Yang Jingyu Wang |
| author_sort | Bo Wen |
| collection | DOAJ |
| description | ABSTRACT Peste des petits ruminants virus (PPRV) is an important pathogen that has long been a significant threat to small ruminant productivity worldwide. Iron metabolism is vital to the host and the pathogen. However, the mechanism underlying host-PPRV interactions from the perspective of iron metabolism and iron-mediated membrane lipid peroxidation has not been reported thus far. In this study, we identified a novel host long-noncoding RNA (lncRNA), APR, that impairs PPRV infectivity by sponging miR-3955-5p, a negative microRNA (miRNA) that directly targets the gene encoding the ferritin-heavy chain 1 (FTH1) protein. Importantly, we demonstrated that PPRV infection causes aberrant cellular iron accumulation by increasing transferrin receptor (TFRC) expression and that iron accumulation induces reticulophagy and ferroptosis, which benefits PPRV replication. Moreover, PPRV infection enhanced the localization of cellular iron on the endoplasmic reticulum (ER) and caused ER membrane damage by promoting excess lipid peroxidation to induce reticulophagy. Interestingly, APR decreased PPRV infection-induced accumulation of intracellular Fe2+ via miR-3955-5p/FTH1 axis and ultimately inhibited reticulophagy and ferroptosis. Additionally, our results indicate that interferon regulatory factor 1 promotes APR transcription by positively regulating APR promoter activity after PPRV infection. Taken together, our findings revealed a new pattern of PPRV-host interactions, involving noncoding RNA regulation, iron metabolism, and iron-related membrane lipid peroxidation, which is critical for understanding the host defense against PPRV infection and the pathogenesis of PPRV.IMPORTANCEMany viruses have been demonstrated to engage in iron metabolism to facilitate their replication and pathogenesis. However, the mechanism by which PPRV interacts with host cells from the perspective of iron metabolism, or iron-mediated membrane lipid peroxidation, has not yet been reported. Our data provide the first direct evidence that PPRV infection induces aberrant iron accumulation to promote viral replication and reveal a novel host lncRNA, APR, as a regulator of iron accumulation by promoting FTH1 protein expression. In this study, PPRV infection increased cellular iron accumulation by increasing TFRC expression, and more importantly, iron overload increased viral infectivity as well as promoted ER membrane lipid peroxidation by enhancing the localization of cellular iron on the ER and ultimately induced ferroptosis and reticulophagy. Furthermore, a host factor, the lncRNA APR, was found to decrease cellular iron accumulation by sponging miR-3955-5p, which directly targets the gene encoding the FTH1 protein, thereby attenuating PPRV infection-induced ferroptosis and reticulophagy and inhibiting PPRV infection. Taken together, the results of the present study provide new insight into our understanding of host-PPRV interaction and pathogenesis from the perspective of iron metabolism and reveal potential targets for therapeutics against PPRV infection. |
| format | Article |
| id | doaj-art-db8accd8352d4441a07429e6757d8178 |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | American Society for Microbiology |
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| series | mBio |
| spelling | doaj-art-db8accd8352d4441a07429e6757d81782025-08-20T03:17:58ZengAmerican Society for MicrobiologymBio2150-75112025-04-0116410.1128/mbio.00127-25The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replicationBo Wen0Wenchi Chang1Lulu Yang2Daiyue Lv3Lizhen Wang4Lei Wang5Yanzhao Xu6Jianhe Hu7Ke Ding8Qinghong Xue9Xuefeng Qi10Bo Yang11Jingyu Wang12College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, ChinaCollege of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, ChinaCollege of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, ChinaCollege of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, ChinaCollege of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, ChinaCollege of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, ChinaCollege of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, ChinaCollege of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, ChinaCollege of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, ChinaChina Institute of Veterinary Drug Control, Beijing, Beijing, ChinaCollege of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, ChinaCollege of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, ChinaCollege of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, ChinaABSTRACT Peste des petits ruminants virus (PPRV) is an important pathogen that has long been a significant threat to small ruminant productivity worldwide. Iron metabolism is vital to the host and the pathogen. However, the mechanism underlying host-PPRV interactions from the perspective of iron metabolism and iron-mediated membrane lipid peroxidation has not been reported thus far. In this study, we identified a novel host long-noncoding RNA (lncRNA), APR, that impairs PPRV infectivity by sponging miR-3955-5p, a negative microRNA (miRNA) that directly targets the gene encoding the ferritin-heavy chain 1 (FTH1) protein. Importantly, we demonstrated that PPRV infection causes aberrant cellular iron accumulation by increasing transferrin receptor (TFRC) expression and that iron accumulation induces reticulophagy and ferroptosis, which benefits PPRV replication. Moreover, PPRV infection enhanced the localization of cellular iron on the endoplasmic reticulum (ER) and caused ER membrane damage by promoting excess lipid peroxidation to induce reticulophagy. Interestingly, APR decreased PPRV infection-induced accumulation of intracellular Fe2+ via miR-3955-5p/FTH1 axis and ultimately inhibited reticulophagy and ferroptosis. Additionally, our results indicate that interferon regulatory factor 1 promotes APR transcription by positively regulating APR promoter activity after PPRV infection. Taken together, our findings revealed a new pattern of PPRV-host interactions, involving noncoding RNA regulation, iron metabolism, and iron-related membrane lipid peroxidation, which is critical for understanding the host defense against PPRV infection and the pathogenesis of PPRV.IMPORTANCEMany viruses have been demonstrated to engage in iron metabolism to facilitate their replication and pathogenesis. However, the mechanism by which PPRV interacts with host cells from the perspective of iron metabolism, or iron-mediated membrane lipid peroxidation, has not yet been reported. Our data provide the first direct evidence that PPRV infection induces aberrant iron accumulation to promote viral replication and reveal a novel host lncRNA, APR, as a regulator of iron accumulation by promoting FTH1 protein expression. In this study, PPRV infection increased cellular iron accumulation by increasing TFRC expression, and more importantly, iron overload increased viral infectivity as well as promoted ER membrane lipid peroxidation by enhancing the localization of cellular iron on the ER and ultimately induced ferroptosis and reticulophagy. Furthermore, a host factor, the lncRNA APR, was found to decrease cellular iron accumulation by sponging miR-3955-5p, which directly targets the gene encoding the FTH1 protein, thereby attenuating PPRV infection-induced ferroptosis and reticulophagy and inhibiting PPRV infection. Taken together, the results of the present study provide new insight into our understanding of host-PPRV interaction and pathogenesis from the perspective of iron metabolism and reveal potential targets for therapeutics against PPRV infection.https://journals.asm.org/doi/10.1128/mbio.00127-25PPRViron overloadlipid peroxidationlncRNA APRreplication |
| spellingShingle | Bo Wen Wenchi Chang Lulu Yang Daiyue Lv Lizhen Wang Lei Wang Yanzhao Xu Jianhe Hu Ke Ding Qinghong Xue Xuefeng Qi Bo Yang Jingyu Wang The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication mBio PPRV iron overload lipid peroxidation lncRNA APR replication |
| title | The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication |
| title_full | The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication |
| title_fullStr | The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication |
| title_full_unstemmed | The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication |
| title_short | The long noncoding RNA APR attenuates PPRV infection-induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication |
| title_sort | long noncoding rna apr attenuates pprv infection induced accumulation of intracellular iron to inhibit membrane lipid peroxidation and viral replication |
| topic | PPRV iron overload lipid peroxidation lncRNA APR replication |
| url | https://journals.asm.org/doi/10.1128/mbio.00127-25 |
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