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Ho-Xuan, H.* ; Bruckmann, A.* ; Natali, L.* ; Prieto-Garcia, C.* ; Stuke, J.F.M.* ; Brunello, L.* ; Vicente, A.B.* ; Pfab, A.* ; Wesseling, H.* ; Cano-Franco, S.* ; Khatri, A.* ; Larivera, S.* ; Sanz-Martinez, P.* ; de la Cruz-Thea, B.* ; Jacomin, A.C.* ; Prochazka, J.* ; Feederle, R. ; Dötsch, V.* ; Sedlacek, R.* ; Hummer, G.* ; Kaiser, S.* ; Dikic, I.* ; Musri, M.M.* ; Meister, G.* ; Stolz, A.*

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

Cell Rep. 44:116188 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cp: Cell Biology ; Rna Binding ; Ythdf ; Cancer ; Cellular Homeostasis ; Contact Inhibition ; Lysosomal Degradation ; M6a ; Selective Autophagy; Gene-expression; Rna; Phosphorylation; Target
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 44, Issue: 9, Pages: , Article Number: 116188 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) CF Monoclonal Antibodies (CF-MAB)
Grants Max Planck Society
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Bayerische Forschungsstiftung (FORTiTher)
Hessian Ministry for Science and the Arts (HMWK)
Czech Academy of Sciences
Ministry of Education, Youth and Sports of the Czech Republic
Boehringer Ingelheim Foundation