MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1.

Signaling through RAS/MAP kinase pathway is central to biology. ERK has long been perceived as the only substrate for MEK. Here, we report that HSF1, the master regulator of the proteotoxic stress response, is a new MEK substrate. Beyond mediating cell-environment interactions, the MEK-HSF1 regulation impacts malignancy. In tumor cells, MEK blockade inactivates HSF1 and thereby provokes proteomic chaos, presented as protein destabilization, aggregation, and, strikingly, amyloidogenesis. Unlike their non-transformed counterparts, tumor cells are particularly susceptible to proteomic perturbation and amyloid induction. Amyloidogenesis is tumor suppressive, reducing in vivo melanoma growth and contributing to the potent anti-neoplastic effects of proteotoxic stressors. Our findings unveil a key biological function of the oncogenic RAS-MEK signaling in guarding proteostasis and suppressing amyloidogenesis. Thus, proteomic instability is an intrinsic feature of malignant state, and disrupting the fragile tumor proteostasis to promote amyloidogenesis may be a feasible therapeutic strategy.

HSF1: Guardian of Proteostasis in Cancer.

Proteomic instability is causally related to human diseases. In guarding proteome stability, the heat shock factor 1 (HSF1)-mediated proteotoxic stress response plays a pivotal role. Contrasting with its beneficial role of enhancing cell survival, recent findings have revealed a compelling pro-oncogenic role for HSF1. However, the mechanisms underlying the persistent activation and function of HSF1 within malignancy remain poorly understood. Emerging evidence reveals that oncogenic signaling mobilizes HSF1 and that cancer cells rely on HSF1 to avert proteomic instability and repress tumor-suppressive amyloidogenesis. In aggregate, these new developments suggest that cancer cells endure chronic proteotoxic stress and that proteomic instability is intrinsically associated with the malignant state, a characteristic that could be exploited to combat cancer.

HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth.

To cope with proteotoxic stress, cells attenuate protein synthesis. However, the precise mechanisms underlying this fundamental adaptation remain poorly defined. Here we report that mTORC1 acts as an immediate cellular sensor of proteotoxic stress. Surprisingly, the multifaceted stress-responsive kinase JNK constitutively associates with mTORC1 under normal growth conditions. On activation by proteotoxic stress, JNK phosphorylates both RAPTOR at S863 and mTOR at S567, causing partial disintegration of mTORC1 and subsequent translation inhibition. Importantly, HSF1, the central player in the proteotoxic stress response (PSR), preserves mTORC1 integrity and function by inactivating JNK, independently of its canonical transcriptional action. Thereby, HSF1 translationally augments the PSR. Beyond promoting stress resistance, this intricate HSF1-JNK-mTORC1 interplay, strikingly, regulates cell, organ and body sizes. Thus, these results illuminate a unifying mechanism that controls stress adaptation and growth.