YTHDF proteins and m6A-RNA clients undergo autophagic turnover during contact inhibition

Ho-Xuan, Hung; Bruckmann, Astrid; Natali, Lautaro; Prieto-Garcia, Cristian; Stuke, Jan F.M.; Brunello, Lorene; Vicente, Alexandre; Pfab, Alexander; Wesseling, Hagen; Cano-Franco, Sara; Khatri, Anshu; Larivera, Simone; Sanz-Martinez, Pablo; Cruz-Thea, Benjamin de la; Jacomin, Anne-Claire; Prochazka, Jan; Feederle, Regina; Dötsch, Volker; Sedlacek, Radislav; Hummer, Gerhard; Kaiser, Stefanie; Dikic, Ivan; Musri, Melina M.; Meister, Gunter und Stolz, Alexandra (2025): YTHDF proteins and m6A-RNA clients undergo autophagic turnover during contact inhibition. In: Cell Reports, Bd. 44, Nr. 9, 116188

Abstract

Highlights

• YTHDFs are downregulated upon contact inhibition by constant autophagic turnover

• YTHDF2 selectively interacts with GABARAP L2 in cells

• YTHDF2 serves as a receptor for m6A-RNA co-sequestration into autophagosomes

• Depletion of YTHDF proteins induces cancer-specific cell death

Summary

The YTHDF protein family plays a critical role in cancer development by recognizing and regulating the stability of N6-methyladenosine (m6A)-modified RNA. Here, we reveal an autophagy-dependent mechanism controlling YTHDF protein levels. Using contact inhibition as a cellular model system, we show YTHDF proteins to be rapidly degraded, coinciding with increased autophagy and decreased mTOR activity. Upon pharmacological mTOR inhibition, YTHDF2 is also downregulated via lysosomal degradation. YTHDF2 selectively interacts with the autophagy modifier GABARAP L2 through LC3-interacting region (LIR) motifs in its unstructured N- and C-terminal regions. Autophagic YTHDF2 downregulation results in the co-degradation of its bound m6A-modified RNA clients. While YTHDF depletion induces cell death in contact-inhibition-deficient HCT116 cancer cells, contact-inhibited MRC5 and RPE1 cells remain unaffected. Our findings uncover a regulatory pathway that governs YTHDF protein stability with significant implications for cancer biology and cell fate determination and suggest the existence of an autophagy-mediated degradation pathway for m6A-modified RNA.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 22111247
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 242727105
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 259130777
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 514894665
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 515275293
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 512574446