AI Article Synopsis
- Researchers found that inhibiting STAT3 significantly boosts autophagy, both in lab settings and in living organisms.
- Overexpression of different STAT3 variants hampers autophagy during starvation, showing that STAT3 plays a crucial role in regulating this process.
- The study reveals that STAT3 interacts with PKR, and inhibiting STAT3 disrupts this interaction, promoting autophagy through PKR activation and eIF2α phosphorylation.
Article Abstract
In a screen designed to identify novel inducers of autophagy, we discovered that STAT3 inhibitors potently stimulate the autophagic flux. Accordingly, genetic inhibition of STAT3 stimulated autophagy in vitro and in vivo, while overexpression of STAT3 variants, encompassing wild-type, nonphosphorylatable, and extranuclear STAT3, inhibited starvation-induced autophagy. The SH2 domain of STAT3 was found to interact with the catalytic domain of the eIF2α kinase 2 EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic inhibition of STAT3 stimulated the activating phosphorylation of PKR and consequent eIF2α hyperphosphorylation. Moreover, PKR depletion inhibited autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like palmitate. STAT3-targeting chemicals and palmitate caused the disruption of inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2α phosphorylation, which facilitates autophagy induction. These results unravel an unsuspected mechanism of autophagy control that involves STAT3 and PKR as interacting partners.
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| http://dx.doi.org/10.1016/j.molcel.2012.09.013 | DOI Listing |
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