HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space
9 affiliations
- 1Neuroproteomics, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany
- 2Distributed Algorithms and Supercomputing, Zuse Institute Berlin, Berlin 14195, Germany
- 3Proteomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany
- 4Core Unit Bioinformatics, Berlin Institute of Health at Charité, University Medicine Berlin, Berlin 10117, Germany
- 5Structural Genomics Consortium, University of Toronto, Toronto, ON M5G1L7, Canada
- 6Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G1L7, Canada
- 7Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S3M2, Canada
- 8Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
- 9Allosteric Proteomics, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany
Abstract
Huntingtin-associated protein 40 (HAP40) forms a stable protein complex with huntingtin (HTT). Its cellular function and how HAP40 loss influences mutant HTT (mHTT) abundance and pathobiology are currently unclear. Here, using diverse cellular models and omics methods, we demonstrate that HAP40 is an obligate interaction partner of HTT and through its binding controls HTT interactions and the abundance of HTT-associated proteins, indicating that it functions as a HTT interaction regulatory unit. Also, loss of HAP40 in mHTT-expressing striatal cells impairs autophagic protein degradation and triggers transcriptional activation of the CLEAR network, demonstrating that it functions as a proteostasis regulator that acts on quality control pathways. Finally, mHTT-expressing cells lacking HAP40 showed increased secretion of a ~205 kDa mHTT fragment through an endoplasmic reticulum (ER)/Golgi-associated route, indicating that striatal cells reduce intracellular mHTT-induced proteotoxicity through activation of secretory pathways. Together, these results establish HAP40 as a critical proteostasis regulator that through controlling HTT interactions maintains cellular homeostasis.
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BibTeX
@article{ramos2026hap40,
title = {{HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space}},
author = {Eduardo Silva Ramos and Annett Boeddrich and Christian Haenig and Philipp Trepte and Orchid Ammar and Christopher Secker and Oliver Popp and Andranik Ivanov and Stephanie Beetz and Leonard Roth and Roxane M. Papawassiliou and Luisanna C. Hernandez Jeppesen and Theo Wallenfang and Brandon Keith and Rachel J. Harding and Franziska Schindler and Tomas Koudelka and Nadine Scharek and Martina Zenkner and Nancy Neuendorf and Sabrina Golusik and Philipp Mertins and Ilaria Piazza and Sigrid Schnoegl and Erich E. Wanker},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2611301123},
url = {https://doi.org/10.1073/pnas.2611301123},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space
AU - Eduardo Silva Ramos
AU - Annett Boeddrich
AU - Christian Haenig
AU - Philipp Trepte
AU - Orchid Ammar
AU - Christopher Secker
AU - Oliver Popp
AU - Andranik Ivanov
AU - Stephanie Beetz
AU - Leonard Roth
AU - Roxane M. Papawassiliou
AU - Luisanna C. Hernandez Jeppesen
AU - Theo Wallenfang
AU - Brandon Keith
AU - Rachel J. Harding
AU - Franziska Schindler
AU - Tomas Koudelka
AU - Nadine Scharek
AU - Martina Zenkner
AU - Nancy Neuendorf
AU - Sabrina Golusik
AU - Philipp Mertins
AU - Ilaria Piazza
AU - Sigrid Schnoegl
AU - Erich E. Wanker
PY - 2026
DA - 2026/10/22
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2611301123
UR - https://doi.org/10.1073/pnas.2611301123
AB - Huntingtin-associated protein 40 (HAP40) forms a stable protein complex with huntingtin (HTT). Its cellular function and how HAP40 loss influences mutant HTT (mHTT) abundance and pathobiology are currently unclear. Here, using diverse cellular models and omics methods, we demonstrate that HAP40 is an obligate interaction partner of HTT and through its binding controls HTT interactions and the abundance of HTT-associated proteins, indicating that it functions as a HTT interaction regulatory unit. Also, loss of HAP40 in mHTT-expressing striatal cells impairs autophagic protein degradation and triggers transcriptional activation of the CLEAR network, demonstrating that it functions as a proteostasis regulator that acts on quality control pathways. Finally, mHTT-expressing cells lacking HAP40 showed increased secretion of a ~205 kDa mHTT fragment through an endoplasmic reticulum (ER)/Golgi-associated route, indicating that striatal cells reduce intracellular mHTT-induced proteotoxicity through activation of secretory pathways. Together, these results establish HAP40 as a critical proteostasis regulator that through controlling HTT interactions maintains cellular homeostasis.
SN - 0027-8424
SN - 1091-6490
ER -