HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection

Abstract

The role of proteomic instability in cancer, particularly amyloidogenesis, remains obscure. Heat shock factor 1 (HSF1) transcriptionally governs the proteotoxic stress response to suppress proteomic instability and enhance survival. Paradoxically, HSF1 promotes oncogenesis. Here, we report that AKT activates HSF1 via Ser²³⁰ phosphorylation. In vivo, HSF1 enables megalencephaly and hepatomegaly, which are driven by hyperactive phosphatidylinositol 3-kinase/AKT signaling. Hsf1 deficiency exacerbates amyloidogenesis and elicits apoptosis, thereby countering tissue overgrowth. Unexpectedly, HSF1 physically neutralizes soluble amyloid oligomers (AOs). Beyond impeding amyloidogenesis, HSF1 shields HSP60 from direct assault by AOs, averting HSP60 destabilization, collapse of the mitochondrial proteome, and, ultimately, mitophagy and apoptosis. The very same mechanism occurs in Alzheimer's disease. These findings suggest that amyloidogenesis may be a checkpoint mechanism that constrains uncontrolled growth and safeguards tissue homeostasis, congruent with its emerging tumor-suppressive function. HSF1, by acting as an anti-amyloid factor, promotes overgrowth syndromes and cancer but may suppress neurodegenerative disorders.