The intimate connection between proteotoxic stress response and inflammation in human cells.

What is it about?

Imbalance in protein homeostasis by various stressors is resolved by induction of heat shock proteins (HSPs) by HSF1. However involvement of other non classical HSPs in this process has been emphasized by different studies. Upregulation of NF-κB activity during heat shock recovery has been shown to rescue the cells from the lethality of protein aggregation by inducing the autophagy. Here we show that, induction of TNF-α during proteotoxic stress response by HSF1 drives the induction of NF-κB signalling pathway. Our finding provides a first instance where HSF1 regulates the induction of a gene by recruiting a multiprotein activation complex at the 3’-UTR region of TNF-α. This study highlights a new axis of connection between proteotoxic stress response and inflammatory signal in human cells.

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Why is it important?

Our study revealed that TNF-α (a crucial proinflammatory gene) is induced by HSF1 during the proteotxic stress, independent of the canonical TNF-α inducers NF-κB or nuclear factor of activated T cells (NFAT). Our results conclude that TNF-α thus produced pioneers the activation of NF-κB signaling cascade, hence connecting proteotoxic stress with inflammation. Consumption of moderate and binge alcohol, arsenic-contaminated water, or cigarette smoke has been shown to disrupt the protein homeostasis and induces inflammatory response in cells and organisms that has been correlated with cancer disease progression. Data presented here emphasized that TNF-α is the key initiator of the cross-talk between the inflammation and proteotoxic stress response pathways. TNF-α, being an essential regulator of inflammation, has been considered as a potential drug target to ameliorate many inflammatory disorders. This study reinforces the idea of inhibition of HSF1 as a therapeutic target to control cellular inflammation and its associated diseases that take a heavy toll on human lives.

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