The retinal pigment epithelium (RPE) sustains lifelong proteostasis under chronic stress, yet how post-mitotic cells activate macroautophagy/autophagy when canonical kinase pathways suppress it remains unresolved. Here we demonstrate that AKT1 (protein kinase B alpha), drives autophagy through a non-canonical transcriptional mechanism triggered by isoform imbalance. In RPE and age-related macular degeneration (AMD) models, AKT2 (protein kinase B beta) hyperactivation destabilizes MTORC2 (mechanistic target of rapamycin complex 2) and engages RPS6KB/S6K (ribosomal protein S6 kinase beta) -mediated IRS-1 (insulin Receptor Substrate 1) inhibition, creating a feedforward autophagic arrest. Compensatory AKT1 activation via MTORC2 phosphorylates TERT (telomerase reverse transcriptase) at serine 824, driving nuclear translocation that is independent of telomere maintenance. In the nucleus, TERT assembles with FOXO3 (forkhead Box O3) and MYC (MYC proto-oncogene, bHLH transcription factor) into a tripartite transcriptional complex that occupies the EIF2AK3/PERK promoter (eukaryotic translation initiation factor 2-alpha kinase 3/ protein kinase R-like endoplasmic reticulum kinase), enabling EIF2AK3 transcriptional activation. This activity converts the unfolded protein response from pro-apoptotic to cytoprotective: EIF2AK3-ATF4 (activating transcription factor 4) signaling promotes core autophagy machinery biogenesis and selective ERphagy through the receptors TEX264 (testis expressed 264) and CCPG1(cell cycle progression 1), which prevents pathological EIF2AK3 clustering and preserves tubular ER architecture in diseased RPE. Using C. elegans phosphorylation-deficient mutants, mouse models and AMD patient iPSC-RPE, we establish that AKT1-mediated TERT phosphorylation is an evolutionarily conserved prerequisite for FOXO/DAF-16 nuclear function and lysosomal homeostasis in post-mitotic cells, offering therapeutic potential through targeted pharmacologic inhibition of AKT2.Abbreviations: ACTB: actin, beta; AKT1: AKT serine/threonine kinase 1; AKT2: AKT serine/threonine kinase 2; ALP: autophagy-lysosomal pathway; AMD: age-related macular degeneration, ATF4: activating transcription factor 4; ATG3: autophagy related 3; ATG4B: autophagy related 4B cysteine peptidase; ATG7: autophagy related 7; CCPG1: cell cycle progression 1; CFH: complement factor H; C57BL/6J: C57 black 6J; DMSO: dimethyl sulfoxide; MYC: MYC proto-oncogene, bHLH transcription factor; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE-1α: endoplasmic reticulum to nucleus signaling 1; ERphagy: endoplasmic reticulum-selective autophagy; FOXO1: forkhead box O1; FOXO3: forkhead box O3; iPSC-RPE: induced pluripotent stem cell-derived retinal pigment epithelium; ITGB1/integrin β1: integrin subunit beta 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPKAP1/SIN1: MAPK associated protein 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; MTORC2: MTOR complex 2; PBS: phosphate-buffered saline; PI3K: phosphoinositide 3-kinase; RICTOR: RPTOR independent companion of MTOR complex 2; RPE: retinal pigment epithelium; RPTOR: regulatory associated protein of MTOR complex 1; SQSTM1/p62: sequestosome 1; TERT: telomerase reverse transcriptase; TEX264: testis expressed 264, ER-phagy receptor; UPR: unfolded protein response; VCL: vinculin; WT: wild type.
