YTHDF proteins and m<SUP>6</SUP>A-RNA clients undergo autophagic turnover during contact inhibition

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F25%3A00640524" target="_blank" >RIV/68378050:_____/25:00640524 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1016/j.celrep.2025.116188" target="_blank" >https://doi.org/10.1016/j.celrep.2025.116188</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.celrep.2025.116188" target="_blank" >10.1016/j.celrep.2025.116188</a>

Jazyk výsledku

angličtina

Název v původním jazyce

YTHDF proteins and m<SUP>6</SUP>A-RNA clients undergo autophagic turnover during contact inhibition

Popis výsledku v původním jazyce

The YTHDF protein family plays acritical role in cancer development by recognizing and regulating the stability of N6-methyladenosine (m(6)A)-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 m(6)A-modi-fied 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 m(6)A-modified RNA.

Název v anglickém jazyce

YTHDF proteins and m<SUP>6</SUP>A-RNA clients undergo autophagic turnover during contact inhibition

Popis výsledku anglicky

The YTHDF protein family plays acritical role in cancer development by recognizing and regulating the stability of N6-methyladenosine (m(6)A)-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 m(6)A-modi-fied 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 m(6)A-modified RNA.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LM2023036" target="_blank" >LM2023036: České centrum pro fenogenomiku</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cell Reports

ISSN

2639-1856

e-ISSN

—

Svazek periodika

44

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

30

Strana od-do

116188

Kód UT WoS článku

001595337400004

EID výsledku v databázi Scopus

2-s2.0-105013848046