m6A-binding YTHDF proteins promote stress granule formation

Ye Fu; Xiaowei Zhuang

doi:10.1038/s41589-020-0524-y

m⁶A-binding YTHDF proteins promote stress granule formation

Nat Chem Biol. 2020 Sep;16(9):955-963. doi: 10.1038/s41589-020-0524-y. Epub 2020 May 25.

Authors

Ye Fu^{1

2}, Xiaowei Zhuang^{3

4

5}

Affiliations

¹ Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
² Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
³ Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. zhuang@chemistry.harvard.edu.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. zhuang@chemistry.harvard.edu.
⁵ Department of Physics, Harvard University, Cambridge, MA, USA. zhuang@chemistry.harvard.edu.

Abstract

Diverse RNAs and RNA-binding proteins form phase-separated, membraneless granules in cells under stress conditions. However, the role of the prevalent mRNA methylation, m⁶A, and its binding proteins in stress granule (SG) assembly remain unclear. Here, we show that m⁶A-modified mRNAs are enriched in SGs, and that m⁶A-binding YTHDF proteins are critical for SG formation. Depletion of YTHDF1/3 inhibits SG formation and recruitment of mRNAs to SGs. Both the N-terminal intrinsically disordered region and the C-terminal m⁶A-binding YTH domain of YTHDF proteins are important for SG formation. Super-resolution imaging further reveals that YTHDF proteins appear to be in a super-saturated state, forming clusters that often reside in the periphery of or at the junctions between SG core clusters, and potentially promote SG formation by reducing the activation energy barrier and critical size for SG condensate formation. Our results suggest a new function of the m⁶A-binding YTHDF proteins in regulating SG formation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives*
Adenine / metabolism
Cell Line, Tumor
Cytoplasmic Granules / genetics
Cytoplasmic Granules / metabolism*
DNA Helicases / genetics
DNA Helicases / metabolism
Humans
Methyltransferases / genetics
Methyltransferases / metabolism
Mutation
Oxidative Stress
Poly-ADP-Ribose Binding Proteins / genetics
Poly-ADP-Ribose Binding Proteins / metabolism
Protein Domains
RNA Helicases / genetics
RNA Helicases / metabolism
RNA Recognition Motif Proteins / genetics
RNA Recognition Motif Proteins / metabolism
RNA, Messenger / chemistry
RNA, Messenger / metabolism
RNA-Binding Proteins / chemistry
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*

Substances

Poly-ADP-Ribose Binding Proteins
RNA Recognition Motif Proteins
RNA, Messenger
RNA-Binding Proteins
YTHDF1 protein, human
YTHDF3 protein, human
Methyltransferases
METTL3 protein, human
DNA Helicases
G3BP1 protein, human
RNA Helicases
Adenine
6-methyladenine

Abstract

Publication types

MeSH terms

Substances

Grants and funding