Year: 2025
Type: article
Abstract: BACKGROUND: Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy that plays a key role in the regulation of cellular clearance pathways. TFEB is regulated via a complex array of post-translational modifications (PTMs) that limit or enhance its activity. METHOD: We generated and analyzed a transgenic mouse line with neuronal expression of a TFEB transgene modified to resist inhibitory regulation. We also used a combination of kinome screening, biochemical assays, and protein modification to identify proteins relevant in TFEB turnover and function. RESULT: TFEB mice have a significantly elongated lifespan and improved metabolism, immune function, and liver health, indicating a parallel extension of healthspan. We identify IKK (inhibitor of κB kinase) as a TFEB direct modifier. IKK-mediated phosphorylation of TFEB triggers TFEB ubiquitination by the E3 ligase β-TrCP2 (β-Transducin repeat-containing protein 2), which tags TFEB for proteasomal degradation. Modified TFEB constructs that abolish phosphorylation by IKK or ubiquitination by β-TrCP2 show much increased stability, while remaining sensitive to autophagy- or stress-related stimuli. These stabilized constructs drive increased expression of TFEB target genes and promote clearance of tau aggregates in a model of Alzheimer's disease. CONCLUSION: These findings position TFEB as a promising target for interventions in aging and neurodegeneration and highlight the IKK-TFEB axis as a therapeutic entry point in Alzheimer's pathology.
Source: Alzheimer s & Dementia
Author: Marco Sardiello
Institution: Washington University in St. Louis
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
OpenAlex ID: W7116961775
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