Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity.
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.
INSERM, U848, 94805 Villejuif, France.
Shensi
S
Shen
Mireia
M
Niso-Santano
Sandy
S
Adjemian
Tetsuo
T
Takehara
Shoaib Ahmad
SA
Malik
Hervé
H
Minoux
Sylvie
S
Souquere
Guillermo
G
Mariño
Sylvie
S
Lachkar
Laura
L
Senovilla
Lorenzo
L
Galluzzi
Oliver
O
Kepp
Gérard
G
Pierron
Maria Chiara
MC
Maiuri
Hayato
H
Hikita
Romano
R
Kroemer
Guido
G
Kroemer
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000201:enzymology*; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019892:eIF-2 Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
D015852:Eukaryotic Initiation Factor-2; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D019308:Palmitic Acid; D019892:eIF-2 Kinase