Starvation-induced HSC70 O-GlcNAcylation activates chaperone-mediated autophagy.
Level 5 - mechanism / opinion, no new human data
Mechanistic in vitro and proteomic laboratory study without human subjects
PubMed 42142583 · doi:10.1016/j.jbc.2026.113165
What was done
The authors investigated the molecular mechanism linking starvation to chaperone-mediated autophagy (CMA) activation. Using biochemical assays and label-free quantitative mass spectrometry, they analyzed the interaction between HSC70 and O-GlcNAc transferase under glucose depletion, validated HSC70 O-GlcNAcylation at T430, and compared the interactomes of wild-type HSC70 (HSC70-WT) and mutant HSC70-T430A to identify potential CMA substrates, including Ataxin-10.
What was found
The abstract reports directional findings without numerical values. Glucose depletion increased HSC70 interaction with O-GlcNAc transferase and upregulated HSC70 O-GlcNAcylation at T430. This modification reduced HSC70 stability while increasing binding to known CMA substrates (such as PKM2). Mass spectrometry identified Ataxin-10 as a novel CMA client bearing a KFERQ motif, and the HSC70-T430A mutation decreased binding to Ataxin-10.
Why it matters
These findings uncover a nutrient-sensing biochemical switch where starvation-driven O-GlcNAcylation of HSC70 directly activates CMA and expands the catalog of known CMA substrates to include Ataxin-10.
Limits
This is purely bench-based preclinical research with no in vivo or human data. The abstract provides no quantitative metrics, effect sizes, or sample sizes for the assays performed. The functional impact of Ataxin-10 degradation in disease models was not evaluated.