PI3K/AKT Signaling Activates HSF1 to Preserve Proteostasis and Sustain Growth

Zijian Tang


Signaling through oncogenic PI3K/AKT kinase pathway is crucial to cell and organ growth. Phosphorylation by AKT has long been perceived as a key factor to enhance protein biosynthesis that enables cell growth and survival. Here, we report that HSF1, the master regulator of the proteotoxic stress response (PSR), is a new AKT substrate. Beyond mobilizing the PSR under heat shock, the AKT-mediated HSF1 activation supports robust growth. In a mouse model of human megalencephaly, expression of a constitutively active PI3KCAsuffices to drive brain overgrowth, and strikingly, it also provokes proteomic chaos including protein aggregation and amyloidogenesis. Deletion of Hsf1in this model reduces the brain size and prolongs the mice survival. Furthermore, HSF1 maintains mitochondrial proteome homeostasis and prevents cell death by protecting the key mitochondrial chaperone HSP60 from aggregation. Independently of its transcriptional activity, HSF1 sequesters amyloid oligomers away from HSP60 through physical interactions. Together, our findings unveil three novel aspects of HSF1 biology: 1) HSF1 is a new substrate of AKT kinase; 2) HSF1 supports tissue overgrowth by balancing the protein quality and quantity; 3) HSF1 not only prevents amyloidogenesis but also suppresses amyloid-induced cellular toxicity.