A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy

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.