The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway
Abstract Rafeesome, a newly identified multivesicular body (MVB)-like organelle, forms through the fusion of RAB22A-mediated ER-derived noncanonical autophagosomes with RAB22A-positive early endosomes. However, the mechanism underlying the formation of RAB22A-mediated noncanonical autophagosomes rem...
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| Format: | Article |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-025-00792-2 |
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| author | Xueping Zheng Dongmei Fang Hao Shan Beibei Xiao Denghui Wei Yingyi Ouyang Lanqing Huo Zhonghan Zhang Yuanzhong Wu Ruhua Zhang Tiebang Kang Ying Gao |
| author_facet | Xueping Zheng Dongmei Fang Hao Shan Beibei Xiao Denghui Wei Yingyi Ouyang Lanqing Huo Zhonghan Zhang Yuanzhong Wu Ruhua Zhang Tiebang Kang Ying Gao |
| author_sort | Xueping Zheng |
| collection | DOAJ |
| description | Abstract Rafeesome, a newly identified multivesicular body (MVB)-like organelle, forms through the fusion of RAB22A-mediated ER-derived noncanonical autophagosomes with RAB22A-positive early endosomes. However, the mechanism underlying the formation of RAB22A-mediated noncanonical autophagosomes remains unclear. Herein, we report a secretory ER-phagy pathway in which the assembly of RAB22A/TMEM33/RTN4 induces the clustering of high-molecular-weight RTN4 oligomers, leading to ER membrane remodeling. This remodeling drives the biogenesis of ER-derived RTN4-positive noncanonical autophagosomes, which are ultimately secreted as TMEM33-marked RAB22A-induced extracellular vesicles (R-EVs) via Rafeesome. Specifically, RAB22A interacts with the tubular ER membrane protein TMEM33, which binds to the TM2 domain of the ER-shaping protein RTN4, promoting RTN4 homo-oligomerization and thereby generating RTN4-enriched microdomains. Consequently, the RTN4 microdomains may induce high curvature of the ER, facilitating the bud scission of RTN4-positive vesicles. These vesicles are transported by ATG9A and develop into isolation membranes (IMs), which are then anchored by LC3-II, a process catalyzed by the ATG12-ATG5-ATG16L1 complex, allowing them to grow into sealed RTN4 noncanonical autophagosome. While being packaged into these ER-derived intermediate compartments, ER cargoes bypass lysosomal degradation and are directed to secretory autophagy via the Rafeesome-R-EV route. Our findings reveal a secretory ER-phagy pathway initiated by the assembly of RAB22A/TMEM33/RTN4, providing new insights into the connection between ER-phagy and extracellular vesicles. |
| format | Article |
| id | doaj-art-aa67f47be0af45c8a8906e5e90324b73 |
| institution | OA Journals |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-aa67f47be0af45c8a8906e5e90324b732025-08-20T02:10:49ZengNature Publishing GroupCell Discovery2056-59682025-04-0111111610.1038/s41421-025-00792-2The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathwayXueping Zheng0Dongmei Fang1Hao Shan2Beibei Xiao3Denghui Wei4Yingyi Ouyang5Lanqing Huo6Zhonghan Zhang7Yuanzhong Wu8Ruhua Zhang9Tiebang Kang10Ying Gao11Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerAbstract Rafeesome, a newly identified multivesicular body (MVB)-like organelle, forms through the fusion of RAB22A-mediated ER-derived noncanonical autophagosomes with RAB22A-positive early endosomes. However, the mechanism underlying the formation of RAB22A-mediated noncanonical autophagosomes remains unclear. Herein, we report a secretory ER-phagy pathway in which the assembly of RAB22A/TMEM33/RTN4 induces the clustering of high-molecular-weight RTN4 oligomers, leading to ER membrane remodeling. This remodeling drives the biogenesis of ER-derived RTN4-positive noncanonical autophagosomes, which are ultimately secreted as TMEM33-marked RAB22A-induced extracellular vesicles (R-EVs) via Rafeesome. Specifically, RAB22A interacts with the tubular ER membrane protein TMEM33, which binds to the TM2 domain of the ER-shaping protein RTN4, promoting RTN4 homo-oligomerization and thereby generating RTN4-enriched microdomains. Consequently, the RTN4 microdomains may induce high curvature of the ER, facilitating the bud scission of RTN4-positive vesicles. These vesicles are transported by ATG9A and develop into isolation membranes (IMs), which are then anchored by LC3-II, a process catalyzed by the ATG12-ATG5-ATG16L1 complex, allowing them to grow into sealed RTN4 noncanonical autophagosome. While being packaged into these ER-derived intermediate compartments, ER cargoes bypass lysosomal degradation and are directed to secretory autophagy via the Rafeesome-R-EV route. Our findings reveal a secretory ER-phagy pathway initiated by the assembly of RAB22A/TMEM33/RTN4, providing new insights into the connection between ER-phagy and extracellular vesicles.https://doi.org/10.1038/s41421-025-00792-2 |
| spellingShingle | Xueping Zheng Dongmei Fang Hao Shan Beibei Xiao Denghui Wei Yingyi Ouyang Lanqing Huo Zhonghan Zhang Yuanzhong Wu Ruhua Zhang Tiebang Kang Ying Gao The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway Cell Discovery |
| title | The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway |
| title_full | The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway |
| title_fullStr | The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway |
| title_full_unstemmed | The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway |
| title_short | The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway |
| title_sort | assembly of rab22a tmem33 rtn4 initiates a secretory er phagy pathway |
| url | https://doi.org/10.1038/s41421-025-00792-2 |
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