Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity - PubMed (original) (raw)

. 2012 Dec 14;48(5):667-80.

doi: 10.1016/j.molcel.2012.09.013. Epub 2012 Oct 17.

Mireia Niso-Santano, Sandy Adjemian, Tetsuo Takehara, Shoaib Ahmad Malik, Hervé Minoux, Sylvie Souquere, Guillermo Mariño, Sylvie Lachkar, Laura Senovilla, Lorenzo Galluzzi, Oliver Kepp, Gérard Pierron, Maria Chiara Maiuri, Hayato Hikita, Romano Kroemer, Guido Kroemer

Affiliations

• PMID: 23084476
• DOI: 10.1016/j.molcel.2012.09.013

Free article

Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity

Shensi Shen et al. Mol Cell. 2012.

Free 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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Comment in

• Autophagy: STAT3 maintains order.
  Du Toit A. Du Toit A. Nat Rev Mol Cell Biol. 2012 Dec;13(12):754. doi: 10.1038/nrm3472. Epub 2012 Nov 15. Nat Rev Mol Cell Biol. 2012. PMID: 23151659 No abstract available.

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