Cell Biology

Inhibit Autophagy, STAT!

Science Signaling  01 Jan 2013:
Vol. 6, Issue 256, pp. ec4
DOI: 10.1126/scisignal.2003913

During stressful conditions, protein translation is suppressed to conserve cellular resources, and this suppression is mediated by the phosphorylation and inhibition of the eukaryotic initiation factor 2α (eIF2α) by various kinases, including protein kinase R (PKR), which is activated by double-stranded RNA. Phosphorylation of eIF2α is required to activate autophagy, a process by which cells degrade proteins and organelles to eliminate damaged cellular constituents and to provide recycled cellular components to maintain cellular metabolism. Shen et al. searched for inducers of autophagy by screening human osteosarcoma U2OS cells with chemical libraries. Various compounds that prevented the tyrosine phosphorylation and activation of STAT3 (signal transducer and activator of transcription 3) increased autophagy, as assessed by enhanced degradation of the autophagic cargo receptor p62 and enhanced accumulation of green fluorescent protein (GFP)–tagged LC3, a protein that is lipidated and associates with autophagosomal membranes. Small interfering RNAs (siRNAs) directed against STAT3 reduced accumulation of red fluorescent protein (RFP)–tagged LC3, an effect that was rescued by a constitutively cytoplasmic form of STAT3 but not by a constitutively nuclear form. Autophagy was increased in the livers of mice with a hepatocyte-specific deletion of Stat3. The kinase activity of PKR was increased in U2OS cells treated with STAT3 inhibitors, and STAT3 coimmunoprecipitated with PKR from U2OS cells, an interaction that was reduced by pharmacological inhibition of STAT3. Forms of STAT3 that could not interact with PKR showed reduced ability to suppress autophagy. Autophagy was not increased by STAT3 inhibitors in mouse embryonic fibroblasts with a knock-in of a nonphosphorylatable form of eIF2α, and phosphorylation of eIF2α induced by STAT3 inhibitors was reduced by transfection of an siRNA directed against PKR. Phosphorylation of eIF2α was suppressed to a comparable extent in U2OS cells by expression of wild-type STAT3 or a STAT3 mutant that could not be tyrosine phosphorylated. Thus, cytoplasmic STAT3 inhibits PKR to suppress autophagy under basal conditions.

S. Shen, M. Niso-Santano, S. Adjemian, T. Takehara, S. A. Malik, H. Minoux, S. Souquere, G. Mariño, S. Lachkar, L. Senovilla, L. Galluzzi, O. Kepp, G. Pierron, M. C. Maiuri, H. Hikita, R. Kroemer, G. Kroemer, Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol. Cell 48, 667–680 (2012). [PubMed]