QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism

Zhicong Zhao; Ying Qing; Lei Dong; Li Han; Dong Wu; Yangchan Li; Wei Li; Jianhuang Xue; Keren Zhou; Miao Sun; Brandon Tan; Zhenhua Chen; Chao Shen; Lei Gao; Andrew Small; Kitty Wang; Keith Leung; Zheng Zhang; Xi Qin; Xiaolan Deng; Qiang Xia; Rui Su; Jianjun Chen

doi:10.1016/j.cell.2023.05.047

QKI shuttles internal m⁷G-modified transcripts into stress granules and modulates mRNA metabolism

Zhicong Zhao, Ying Qing, Lei Dong, Li Han, Dong Wu, Yangchan Li, Wei Li, Jianhuang Xue, Keren Zhou, Miao Sun, Brandon Tan, Zhenhua Chen, Chao Shen, Lei Gao, Andrew Small, Kitty Wang, Keith Leung, Zheng Zhang, Xi Qin, Xiaolan DengQiang Xia, Rui Su, Jianjun Chen

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

N⁷-methylguanosine (m⁷G) modification, routinely occurring at mRNA 5′ cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m⁷G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m⁷G modification remains elusive. Here, we report that mRNA internal m⁷G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m⁷G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m⁷G-modified and QKI-bound mRNA targets with a conserved “GANGAN (N = A/C/U/G)” motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m⁷G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m⁷G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.

Original language	English (US)
Pages (from-to)	3208-3226.e27
Journal	Cell
Volume	186
Issue number	15
DOIs	https://doi.org/10.1016/j.cell.2023.05.047
State	Published - Jul 20 2023

Keywords

G3BP1
METTL1
N-methylguanosine
QKI
drug resistance
mG
mRNA metabolism
mRNA stability
stress granule
translational regulation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2023.05.047

Cite this

Zhao, Z., Qing, Y., Dong, L., Han, L., Wu, D., Li, Y., Li, W., Xue, J., Zhou, K., Sun, M., Tan, B., Chen, Z., Shen, C., Gao, L., Small, A., Wang, K., Leung, K., Zhang, Z., Qin, X., ... Chen, J. (2023). QKI shuttles internal m⁷G-modified transcripts into stress granules and modulates mRNA metabolism. Cell, 186(15), 3208-3226.e27. https://doi.org/10.1016/j.cell.2023.05.047

Zhao, Z, Qing, Y, Dong, L, Han, L, Wu, D, Li, Y, Li, W, Xue, J, Zhou, K, Sun, M, Tan, B, Chen, Z, Shen, C, Gao, L, Small, A, Wang, K, Leung, K, Zhang, Z, Qin, X, Deng, X, Xia, Q, Su, R & Chen, J 2023, 'QKI shuttles internal m⁷G-modified transcripts into stress granules and modulates mRNA metabolism', Cell, vol. 186, no. 15, pp. 3208-3226.e27. https://doi.org/10.1016/j.cell.2023.05.047

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title = "QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism",

abstract = "N7-methylguanosine (m7G) modification, routinely occurring at mRNA 5′ cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved “GANGAN (N = A/C/U/G)” motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.",

keywords = "G3BP1, METTL1, N-methylguanosine, QKI, drug resistance, mG, mRNA metabolism, mRNA stability, stress granule, translational regulation",

author = "Zhicong Zhao and Ying Qing and Lei Dong and Li Han and Dong Wu and Yangchan Li and Wei Li and Jianhuang Xue and Keren Zhou and Miao Sun and Brandon Tan and Zhenhua Chen and Chao Shen and Lei Gao and Andrew Small and Kitty Wang and Keith Leung and Zheng Zhang and Xi Qin and Xiaolan Deng and Qiang Xia and Rui Su and Jianjun Chen",

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doi = "10.1016/j.cell.2023.05.047",

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T1 - QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism

AU - Zhao, Zhicong

AU - Qing, Ying

AU - Dong, Lei

AU - Han, Li

AU - Wu, Dong

AU - Li, Yangchan

AU - Li, Wei

AU - Xue, Jianhuang

AU - Zhou, Keren

AU - Sun, Miao

AU - Tan, Brandon

AU - Chen, Zhenhua

AU - Shen, Chao

AU - Gao, Lei

AU - Small, Andrew

AU - Wang, Kitty

AU - Leung, Keith

AU - Zhang, Zheng

AU - Qin, Xi

AU - Deng, Xiaolan

AU - Xia, Qiang

AU - Su, Rui

AU - Chen, Jianjun

PY - 2023/7/20

Y1 - 2023/7/20

N2 - N7-methylguanosine (m7G) modification, routinely occurring at mRNA 5′ cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved “GANGAN (N = A/C/U/G)” motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.

AB - N7-methylguanosine (m7G) modification, routinely occurring at mRNA 5′ cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved “GANGAN (N = A/C/U/G)” motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.

KW - G3BP1

KW - METTL1

KW - N-methylguanosine

KW - QKI

KW - drug resistance

KW - mG

KW - mRNA metabolism

KW - mRNA stability

KW - stress granule

KW - translational regulation

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M3 - Article

C2 - 37379838

AN - SCOPUS:85165107838

SN - 0092-8674

VL - 186

SP - 3208-3226.e27

JO - Cell

JF - Cell

IS - 15

ER -