NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression
Abstract Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitros...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55788-5 |
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| author | Shuangyan Li Lishan Yan Chaoying Li Lijuan Lou Fengjiao Cui Xiao Yang Fuchu He Ying Jiang |
| author_facet | Shuangyan Li Lishan Yan Chaoying Li Lijuan Lou Fengjiao Cui Xiao Yang Fuchu He Ying Jiang |
| author_sort | Shuangyan Li |
| collection | DOAJ |
| description | Abstract Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl4 induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport. We identify that the 692-854 amino acid region of NPC1’s transmembrane domain is critical for its interaction with TGF-β receptor type-1 (TGFBR1). This interaction prevents the binding of SMAD7 and SMAD ubiquitylation regulatory factors (SMURFs) to TGFBR1, reducing TGFBR1 ubiquitylation and degradation, thus enhancing its stability. Notably, the NPC1 (P691S) mutant, which is defective in cholesterol transport, still binds TGFBR1, underscoring a cholesterol-independent mechanism. These findings highlight a cholesterol transport-independent mechanism by which NPC1 contributes to the stability of TGFBR1 in HCC and suggest potential therapeutic strategies targeting NPC1 for HCC treatment. |
| format | Article |
| id | doaj-art-894a2f4023144e7798ad413437e71a18 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-894a2f4023144e7798ad413437e71a182025-01-12T12:31:44ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55788-5NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progressionShuangyan Li0Lishan Yan1Chaoying Li2Lijuan Lou3Fengjiao Cui4Xiao Yang5Fuchu He6Ying Jiang7School of Life Sciences, Tsinghua UniversityState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsAbstract Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl4 induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport. We identify that the 692-854 amino acid region of NPC1’s transmembrane domain is critical for its interaction with TGF-β receptor type-1 (TGFBR1). This interaction prevents the binding of SMAD7 and SMAD ubiquitylation regulatory factors (SMURFs) to TGFBR1, reducing TGFBR1 ubiquitylation and degradation, thus enhancing its stability. Notably, the NPC1 (P691S) mutant, which is defective in cholesterol transport, still binds TGFBR1, underscoring a cholesterol-independent mechanism. These findings highlight a cholesterol transport-independent mechanism by which NPC1 contributes to the stability of TGFBR1 in HCC and suggest potential therapeutic strategies targeting NPC1 for HCC treatment.https://doi.org/10.1038/s41467-024-55788-5 |
| spellingShingle | Shuangyan Li Lishan Yan Chaoying Li Lijuan Lou Fengjiao Cui Xiao Yang Fuchu He Ying Jiang NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression Nature Communications |
| title | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression |
| title_full | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression |
| title_fullStr | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression |
| title_full_unstemmed | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression |
| title_short | NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression |
| title_sort | npc1 controls tgfbr1 stability in a cholesterol transport independent manner and promotes hepatocellular carcinoma progression |
| url | https://doi.org/10.1038/s41467-024-55788-5 |
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