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YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner

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  • Hyun Jung Hwang

    (Korea Advanced Institute of Science and Technology)

  • Tae Lim Park

    (Korea Advanced Institute of Science and Technology)

  • Hyeong-In Kim

    (Korea Advanced Institute of Science and Technology)

  • Yeonkyoung Park

    (Korea Advanced Institute of Science and Technology)

  • Geunhee Kim

    (Korea Advanced Institute of Science and Technology)

  • Chiyeol Song

    (Korea Advanced Institute of Science and Technology)

  • Won-Ki Cho

    (Korea Advanced Institute of Science and Technology)

  • Yoon Ki Kim

    (Korea Advanced Institute of Science and Technology)

Abstract

YTHDF2 has been extensively studied and typified as an RNA-binding protein that specifically recognizes and destabilizes RNAs harboring N6-methyladenosine (m6A), the most prevalent internal modification found in eukaryotic RNAs. In this study, we unravel the m6A-independent role of YTHDF2 in the formation of an aggresome, where cytoplasmic protein aggregates are selectively sequestered upon failure of protein homeostasis mediated by the ubiquitin-proteasome system. Downregulation of YTHDF2 in HeLa cells reduces the circularity of aggresomes and the rate of movement of misfolded polypeptides, inhibits aggresome formation, and thereby promotes cellular apoptosis. Mechanistically, YTHDF2 is recruited to a misfolded polypeptide-associated complex composed of UPF1, CTIF, eEF1A1, and DCTN1 through its interaction with UPF1. Subsequently, YTHDF2 increases the interaction between the dynein motor protein and the misfolded polypeptide-associated complex, facilitating the diffusion dynamics of the movement of misfolded polypeptides toward aggresomes. Therefore, our data reveal that YTHDF2 is a cellular factor involved in protein quality control.

Suggested Citation

  • Hyun Jung Hwang & Tae Lim Park & Hyeong-In Kim & Yeonkyoung Park & Geunhee Kim & Chiyeol Song & Won-Ki Cho & Yoon Ki Kim, 2023. "YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42015-w
    DOI: 10.1038/s41467-023-42015-w
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