Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL.
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| Titel: | Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL. |
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| Autoren: | Luo D; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China; Genetic Diseases Key Laboratory of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China., Zheng J; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China; Genetic Diseases Key Laboratory of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China., Lv S; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China; Genetic Diseases Key Laboratory of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China., Sheng R; College of Life and Health Science, Northeastern University, Shenyang, China., Chen M; Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China., He X; The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Department of Neurology, Harvard Medical School, Boston, United States., Zhang X; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China; Genetic Diseases Key Laboratory of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.; Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. |
| Quelle: | ELife [Elife] 2025 Oct 10; Vol. 14. Date of Electronic Publication: 2025 Oct 10. |
| Publikationsart: | Journal Article |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012- |
| MeSH-Schlagworte: | Endocytosis* , Frizzled Receptors*/metabolism , Ubiquitin-Protein Ligases*/metabolism , Dishevelled Proteins*/metabolism , Wnt Proteins*/metabolism , Thrombospondins*/metabolism , DNA-Binding Proteins*/metabolism, Humans ; Proteolysis ; Wnt Signaling Pathway ; HEK293 Cells ; R-Spondins |
| Abstract: | Competing Interests: DL, JZ, SL, RS, MC, XH, XZ No competing interests declared Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins. However, the dependency of RSPO-ZNRF3/RNF43-mediated FZD endocytosis and degradation on Wnt stimulation, as well as the specificity of this degradation for different FZD, remains unclear. Here, we demonstrated that Wnt specifically induces FZD5/8 endocytosis and degradation in a ZNRF3/RNF43-dependent manner. ZNRF3/RNF43 selectively targets FZD5/8 for degradation upon Wnt stimulation. RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8. Wnt promotes the interaction between FZD5 and RNF43. We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling in human cells, which may provide new insights into regenerative medicine and cancer therapy. (© 2025, Luo, Zheng, Lv et al.) |
| Kommentare: | Update of: bioRxiv. 2025 Jun 18:2024.10.18.619000. doi: 10.1101/2024.10.18.619000.. (PMID: 39463927) |
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| Grant Information: | 81870620 National Natural Science Foundation of China |
| Contributed Indexing: | Keywords: DVL; FZD5; FZD8; Frizzled5; Frizzled8; R-Spondin; RNF43; Wnt signaling; ZNRF3; cell biology; developmental biology; human; receptor endocytosis |
| Substance Nomenclature: | 0 (Frizzled Receptors) EC 2.3.2.27 (ZNRF3 protein, human) EC 2.3.2.27 (RNF43 protein, human) EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (Dishevelled Proteins) 0 (Wnt Proteins) 0 (Thrombospondins) 0 (FZD5 protein, human) 0 (RSPO1 protein, human) 0 (DNA-Binding Proteins) 0 (R-Spondins) |
| Entry Date(s): | Date Created: 20251010 Date Completed: 20251010 Latest Revision: 20251013 |
| Update Code: | 20251013 |
| PubMed Central ID: | PMC12513720 |
| DOI: | 10.7554/eLife.103996 |
| PMID: | 41070826 |
| Datenbank: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: DL, JZ, SL, RS, MC, XH, XZ No competing interests declared<br />Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins. However, the dependency of RSPO-ZNRF3/RNF43-mediated FZD endocytosis and degradation on Wnt stimulation, as well as the specificity of this degradation for different FZD, remains unclear. Here, we demonstrated that Wnt specifically induces FZD5/8 endocytosis and degradation in a ZNRF3/RNF43-dependent manner. ZNRF3/RNF43 selectively targets FZD5/8 for degradation upon Wnt stimulation. RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8. Wnt promotes the interaction between FZD5 and RNF43. We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling in human cells, which may provide new insights into regenerative medicine and cancer therapy.<br /> (© 2025, Luo, Zheng, Lv et al.) |
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| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.103996 |