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HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection

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...

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Autores principales: Tang, Zijian, Su, Kuo-Hui, Xu, Meng, Dai, Chengkai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673739/
https://www.ncbi.nlm.nih.gov/pubmed/33177089
http://dx.doi.org/10.1126/sciadv.abc6871
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author Tang, Zijian
Su, Kuo-Hui
Xu, Meng
Dai, Chengkai
author_facet Tang, Zijian
Su, Kuo-Hui
Xu, Meng
Dai, Chengkai
author_sort Tang, Zijian
collection PubMed
description 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 Ser(230) 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.
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spelling pubmed-76737392020-11-24 HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection Tang, Zijian Su, Kuo-Hui Xu, Meng Dai, Chengkai Sci Adv Research Articles 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 Ser(230) 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. American Association for the Advancement of Science 2020-11-11 /pmc/articles/PMC7673739/ /pubmed/33177089 http://dx.doi.org/10.1126/sciadv.abc6871 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Tang, Zijian
Su, Kuo-Hui
Xu, Meng
Dai, Chengkai
HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
title HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
title_full HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
title_fullStr HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
title_full_unstemmed HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
title_short HSF1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
title_sort hsf1 physically neutralizes amyloid oligomers to empower overgrowth and bestow neuroprotection
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673739/
https://www.ncbi.nlm.nih.gov/pubmed/33177089
http://dx.doi.org/10.1126/sciadv.abc6871
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