Abstract
The proteotoxic stress response that safeguards the cellular proteome from various stressors was shown to activate NF-κB signaling pathways (NκBS) with an underlying mechanism that is poorly understood. We show here that the TNF-α gene, a pleiotropic NκBS inducer, is a direct target of heat shock factor 1 (HSF1). Human HSF1 drives this process by assembling a multiprotein activation complex at a heat shock element (HSE) located at the 3'-UTR of the TNF-α gene (HSE5). HSF1 associated with the HSE5 at the TNF-α 3'-UTR communicates with the promoter through chromatin looping by recruiting lymphoid enhancer-binding factor 1 at an adjacent Wnt-responsive element through its transactivation domain. TNF-α thus produced guides the activation of NκBS by acting through TNF-α receptor 1 (TNFR1). Notably, cells with TNFR1-/- background or masked HSE5 through Clustered Regularly Interspaced Short Palindromic Repeats/dead CRISPR-associated protein 9 were defective in NκBS and exhibited marked alteration in cellular biology, which includes loss of ability of cancer cells to migrate, to clear the protein aggregates, and associated toxicity upon heat shock. For the first time, our results suggest that TNF-α thus produced pioneers the proinflammatory signal during proteotoxic stress response with an important implication for inflammation and cancer.-Ali, A., Biswas, A., Pal, M. HSF1 mediated TNF-α production during proteotoxic stress response pioneers proinflammatory signal in human cells.