Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation
Abstract Eukaryotic cells direct toxic misfolded proteins to various quality control pathways based on their chemical properties and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the “aggresome”, a perinuclear inclusion at the microtubul...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62751-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849226164133953536 |
|---|---|
| author | Rui Fang Luolan Bai Bert M. Verheijen Boyan Li Kevin Dong Joao A. Paulo Mengying Zhou Yi-Chi Chu Yuyu Song Michael Y. Sherman Steven Gygi Christine M. Field Timothy J. Mitchison Ying Lu |
| author_facet | Rui Fang Luolan Bai Bert M. Verheijen Boyan Li Kevin Dong Joao A. Paulo Mengying Zhou Yi-Chi Chu Yuyu Song Michael Y. Sherman Steven Gygi Christine M. Field Timothy J. Mitchison Ying Lu |
| author_sort | Rui Fang |
| collection | DOAJ |
| description | Abstract Eukaryotic cells direct toxic misfolded proteins to various quality control pathways based on their chemical properties and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the “aggresome”, a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selective aggresome recruitment remains unclear. To investigate this process, here we reconstitute MTOC-directed aggregate transport in Xenopus laevis egg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking reveals that dynein-mediated aggregate transport is highly episodic, with average velocity positively correlating with aggregate size. Mechanistic modeling suggests that recurrent formation of the dynein transport complex biases larger aggregates towards active transport, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are conferred by aggresome-specific dynein adapters. Coupling an aggresome adapter to polystyrene beads recapitulates positive size selectivity in transport, while recruiting conventional dynein adapters to protein aggregates perturbs aggresome formation and reverses the size selectivity. |
| format | Article |
| id | doaj-art-cb7c230659744fe0ad808efd9908668f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cb7c230659744fe0ad808efd9908668f2025-08-24T11:37:13ZengNature PortfolioNature Communications2041-17232025-08-0116112410.1038/s41467-025-62751-5Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formationRui Fang0Luolan Bai1Bert M. Verheijen2Boyan Li3Kevin Dong4Joao A. Paulo5Mengying Zhou6Yi-Chi Chu7Yuyu Song8Michael Y. Sherman9Steven Gygi10Christine M. Field11Timothy J. Mitchison12Ying Lu13Department of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Neurology, Massachusetts General HospitalDepartment of Molecular Biology, Ariel UniversityDepartment of Cell Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolDepartment of Systems Biology, Harvard Medical SchoolAbstract Eukaryotic cells direct toxic misfolded proteins to various quality control pathways based on their chemical properties and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the “aggresome”, a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selective aggresome recruitment remains unclear. To investigate this process, here we reconstitute MTOC-directed aggregate transport in Xenopus laevis egg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking reveals that dynein-mediated aggregate transport is highly episodic, with average velocity positively correlating with aggregate size. Mechanistic modeling suggests that recurrent formation of the dynein transport complex biases larger aggregates towards active transport, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are conferred by aggresome-specific dynein adapters. Coupling an aggresome adapter to polystyrene beads recapitulates positive size selectivity in transport, while recruiting conventional dynein adapters to protein aggregates perturbs aggresome formation and reverses the size selectivity.https://doi.org/10.1038/s41467-025-62751-5 |
| spellingShingle | Rui Fang Luolan Bai Bert M. Verheijen Boyan Li Kevin Dong Joao A. Paulo Mengying Zhou Yi-Chi Chu Yuyu Song Michael Y. Sherman Steven Gygi Christine M. Field Timothy J. Mitchison Ying Lu Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation Nature Communications |
| title | Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation |
| title_full | Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation |
| title_fullStr | Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation |
| title_full_unstemmed | Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation |
| title_short | Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation |
| title_sort | episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation |
| url | https://doi.org/10.1038/s41467-025-62751-5 |
| work_keys_str_mv | AT ruifang episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT luolanbai episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT bertmverheijen episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT boyanli episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT kevindong episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT joaoapaulo episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT mengyingzhou episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT yichichu episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT yuyusong episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT michaelysherman episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT stevengygi episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT christinemfield episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT timothyjmitchison episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation AT yinglu episodictransportofproteinaggregatesachievesapositivesizeselectivityinaggresomeformation |