Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36
Abstract Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to me...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42979-9 |
| _version_ | 1827603371117248512 |
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| author | Shin-Jin Lin Ming-Chieh Lin Tsai-Jung Liu Yueh-Tso Tsai Ming-Ting Tsai Fang-Jen S. Lee |
| author_facet | Shin-Jin Lin Ming-Chieh Lin Tsai-Jung Liu Yueh-Tso Tsai Ming-Ting Tsai Fang-Jen S. Lee |
| author_sort | Shin-Jin Lin |
| collection | DOAJ |
| description | Abstract Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endosomal sorting complex required for transport (ESCRT)-II component VPS36. Arl4A plays a role in prolonging the duration of EGFR ubiquitinylation and deterring endocytosed EGFR transport from endosomes to lysosomes under EGF stimulation. Mechanistically, the Arl4A-VPS36 direct interaction stabilizes VPS36 and ESCRT-III association, affecting subsequent recruitment of deubiquitinating-enzyme USP8 by CHMP2A. Impaired Arl4A-VPS36 interaction enhances EGFR degradation and clearance of EGFR ubiquitinylation. Together, we discover that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting. |
| first_indexed | 2024-03-09T05:38:32Z |
| format | Article |
| id | doaj.art-f33f8b3476f74d23b327abb93e0244c9 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:38:32Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f33f8b3476f74d23b327abb93e0244c92023-12-03T12:27:44ZengNature PortfolioNature Communications2041-17232023-11-0114111810.1038/s41467-023-42979-9Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36Shin-Jin Lin0Ming-Chieh Lin1Tsai-Jung Liu2Yueh-Tso Tsai3Ming-Ting Tsai4Fang-Jen S. Lee5Institute of Molecular Medicine, College of Medicine, National Taiwan UniversityInstitute of Molecular Medicine, College of Medicine, National Taiwan UniversityInstitute of Molecular Medicine, College of Medicine, National Taiwan UniversityInstitute of Molecular Medicine, College of Medicine, National Taiwan UniversityInstitute of Molecular Medicine, College of Medicine, National Taiwan UniversityInstitute of Molecular Medicine, College of Medicine, National Taiwan UniversityAbstract Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endosomal sorting complex required for transport (ESCRT)-II component VPS36. Arl4A plays a role in prolonging the duration of EGFR ubiquitinylation and deterring endocytosed EGFR transport from endosomes to lysosomes under EGF stimulation. Mechanistically, the Arl4A-VPS36 direct interaction stabilizes VPS36 and ESCRT-III association, affecting subsequent recruitment of deubiquitinating-enzyme USP8 by CHMP2A. Impaired Arl4A-VPS36 interaction enhances EGFR degradation and clearance of EGFR ubiquitinylation. Together, we discover that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.https://doi.org/10.1038/s41467-023-42979-9 |
| spellingShingle | Shin-Jin Lin Ming-Chieh Lin Tsai-Jung Liu Yueh-Tso Tsai Ming-Ting Tsai Fang-Jen S. Lee Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36 Nature Communications |
| title | Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36 |
| title_full | Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36 |
| title_fullStr | Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36 |
| title_full_unstemmed | Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36 |
| title_short | Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36 |
| title_sort | endosomal arl4a attenuates egfr degradation by binding to the escrt ii component vps36 |
| url | https://doi.org/10.1038/s41467-023-42979-9 |
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