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Updated: Oct 25, 2026

Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the
Eduardo Silva Ramos1, Annett Boeddrich1, Christian Haenig1
1Neuroproteomics, 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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