A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

Mario Mauthe; Nicole van de Beek; Muriel Mari; Giel Korsten; Parisa Nobari; Kennith B Castelino; Eduardo P de Mattos; Ibtisam Ouhida; Jesse L Dijkstra; Sabine Schipper-Krom; Laura R de la Ballina; Monja R Mueller; Anne Simonsen; Mark S Hipp; Lukas C Kapitein; Harm H Kampinga; Fulvio Reggiori

doi:10.1038/s41556-025-01747-1

A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

Mario Mauthe^*, Nicole van de Beek, Muriel Mari, Giel Korsten, Parisa Nobari, Kennith B Castelino, Eduardo P de Mattos, Ibtisam Ouhida, Jesse L Dijkstra, Sabine Schipper-Krom, Laura R de la Ballina, Monja R Mueller, Anne Simonsen, Mark S Hipp, Lukas C Kapitein, Harm H Kampinga^*, Fulvio Reggiori^*

^*Corresponding author for this work

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Abstract

Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

Original language	English
Pages (from-to)	1448–1464
Number of pages	47
Journal	Nature Cell Biology
Volume	27
Early online date	27-Aug-2025
DOIs	https://doi.org/10.1038/s41556-025-01747-1
Publication status	Published - Sept-2025

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Mauthe, M., van de Beek, N., Mari, M., Korsten, G., Nobari, P., Castelino, K. B., de Mattos, E. P., Ouhida, I., Dijkstra, J. L., Schipper-Krom, S., de la Ballina, L. R., Mueller, M. R., Simonsen, A., Hipp, M. S., Kapitein, L. C., Kampinga, H. H., & Reggiori, F. (2025). A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy. Nature Cell Biology, 27, 1448–1464. https://doi.org/10.1038/s41556-025-01747-1

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title = "A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy",

abstract = "Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.",

author = "Mario Mauthe and \{van de Beek\}, Nicole and Muriel Mari and Giel Korsten and Parisa Nobari and Castelino, \{Kennith B\} and \{de Mattos\}, \{Eduardo P\} and Ibtisam Ouhida and Dijkstra, \{Jesse L\} and Sabine Schipper-Krom and \{de la Ballina\}, \{Laura R\} and Mueller, \{Monja R\} and Anne Simonsen and Hipp, \{Mark S\} and Kapitein, \{Lukas C\} and Kampinga, \{Harm H\} and Fulvio Reggiori",

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year = "2025",

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doi = "10.1038/s41556-025-01747-1",

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volume = "27",

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Mauthe, M, van de Beek, N, Mari, M, Korsten, G, Nobari, P, Castelino, KB, de Mattos, EP, Ouhida, I, Dijkstra, JL, Schipper-Krom, S, de la Ballina, LR, Mueller, MR, Simonsen, A, Hipp, MS, Kapitein, LC, Kampinga, HH & Reggiori, F 2025, 'A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy', Nature Cell Biology, vol. 27, pp. 1448–1464. https://doi.org/10.1038/s41556-025-01747-1

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T1 - A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

AU - Mauthe, Mario

AU - van de Beek, Nicole

AU - Mari, Muriel

AU - Korsten, Giel

AU - Nobari, Parisa

AU - Castelino, Kennith B

AU - de Mattos, Eduardo P

AU - Ouhida, Ibtisam

AU - Dijkstra, Jesse L

AU - Schipper-Krom, Sabine

AU - de la Ballina, Laura R

AU - Mueller, Monja R

AU - Simonsen, Anne

AU - Hipp, Mark S

AU - Kapitein, Lukas C

AU - Kampinga, Harm H

AU - Reggiori, Fulvio

PY - 2025/9

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N2 - Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

AB - Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

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DO - 10.1038/s41556-025-01747-1

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VL - 27

SP - 1448

EP - 1464

JO - Nature Cell Biology

JF - Nature Cell Biology

ER -

A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

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