A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy
Babu, V. S.; Ghosh, S.; Bammidi, S.; Jiwon, R.; Sharma, R.; Meyer, D.; Hose, S.; Pattabiraman, P. P.; Sahel, J.-A.; Kidley, N. J.; Braz, N. F.; Slater, M. J.; Lang, S.; Ghosh, A.; Yi, J.; Sripathi, S.; Rangaramanujam, K.; Bharti, K.; Sinha, D.
Show abstract
Protein kinases canonically suppress autophagy, yet how cells activate autophagy during stress remains unclear. Here we reveal that AKT1 kinase promotes autophagy through a non-canonical pathway. AKT2 loss triggers compensatory AKT1 activation, which phosphorylates telomerase reverse transcriptase (TERT) at Serine 824, driving nuclear translocation. Nuclear TERT assembles with FOXO3 and c-MYC into a transcriptional complex that activates PERK, initiating a feed-forward loop. PERK-ATF4 signaling amplifies autophagy gene transcription while inducing selective ERphagy through receptors TEX264 and CCPG1. Using C. elegans, mouse models, and human iPSCs, we demonstrate this AKT1-TERT-c-MYC-FOXO3 axis is evolutionarily conserved and essential for proteostasis in post-mitotic cells. We developed a first-in-class allosteric AKT2 inhibitor through structure-guided design that selectively triggers beneficial AKT1 compensation, restoring autophagy in diseased cells. These findings reveal a transcriptional mechanism linking AKT1 activation to autophagy and provide a therapeutic strategy for diseases with defective ER quality control.
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