AKT1-phosphorylated TERT assembles a FOXO3-MYC transcriptional complex that drives ERphagy and proteostasis in post-mitotic RPE.

Vishnu Suresh Babu, Sayan Ghosh, Sridhar Bammidi, Ryu Jiwon, Ruchi Sharma, Dominique Meyer, Stacey Hose, Padmanabhan P Pattabiraman, José-Alain Sahel, Nathan J Kidley, Natércia F Braz, Martin J Slater, Stuart Lang, Arkasubhra Ghosh, James T Handa, Ji Yi, Srinivasa Sripathi, Rangaramanujam M Kannan, Kapil Bharti, Debasish Sinha

Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · pubmed

Paper

Abstract

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

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Research summary

AKT1 phosphorylates TERT at serine 824 to drive a FOXO3-MYC transcriptional complex that restores autophagy in post-mitotic RPE cells. This paper is relevant because it identifies a novel, non-canonical mechanism for maintaining proteostasis and cellular health in post-mitotic tissues, which is a fundamental requirement for extending healthy lifespan and preventing age-related degenerative diseases like AMD.

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