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bioRxiv · 10.1101/2025.11.24.690135

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.
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Abstract

The retinal pigment epithelium (RPE) sustains lifelong proteostasis under chronic stress, yet how post-mitotic cells activate autophagy when canonical kinase pathways suppress it remains unresolved. Here we demonstrate that AKT1, conventionally regarded as an autophagy suppressor, drives autophagy through a non-canonical transcriptional mechanism triggered by isoform imbalance. In RPE and age-related macular degeneration (AMD) models, AKT2 hyperactivation destabilizes mTORC2 and engages S6K-mediated IRS-1 inhibition, creating a feedforward autophagic arrest. Compensatory AKT1 activation via mTORC2 phosphorylates telomerase reverse transcriptase (TERT) at Serine 824, driving nuclear translocation that is independent of telomere maintenance. In the nucleus, TERT assembles with FOXO3 and MYC into a tripartite transcriptional complex that occupies the EIF2AK3 promoter, enabling PERK transcriptional activation. This activity converts the unfolded protein response from pro-apoptotic to cytoprotective: PERK-ATF4 signaling drives biogenesis of core autophagy machinery while simultaneously inducing selective ERphagy through the receptors TEX264 and CCPG1, which prevents pathological PERK clustering and preserves tubular ER architecture in diseased RPE. Using C. elegans phosphorylation-deficient mutants, mouse models and AMD patient induced pluripotent stem cell-derived retinal pigment epithelium (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. Pharmacologic targeting of AKT2 with a first-in-class dual-pocket allosteric inhibitor selectively enhances AKT1 compensation, restoring macroautophagic and ERphagy flux across disease models. These findings reveal a kinase-to-transcription axis that reprograms organelle quality control and identify the AKT1-TERT-PERK-ATF4 pathway as a therapeutic target in proteostasis-driven disease.

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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.. 2025-11-26. A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy. https://doi.org/10.1101/2025.11.24.690135

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