HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space.

Loss of HAP40 in mHTT-expressing striatal cells impairs autophagic protein degradation and increases secretion of a ~205 kDa mHTT fragment via an ER/Golgi route.

• Why it matters: HAP40’s role in regulating mutant huntingtin (mHTT) abundance and proteostasis is unclear, limiting understanding of how HTT quality-control pathways are maintained or disrupted.
• What they did: Using diverse cellular models and omics methods, HAP40 was shown as an obligate HTT interaction partner whose binding regulates HTT interactions and the abundance of HTT-associated proteins.
• The result: HAP40 loss activates CLEAR network transcriptional signaling and triggers secretory pathway-mediated release of a ~205 kDa mHTT fragment, implying striatal cells counter proteotoxicity by shifting quality control.