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

Cell, 2023 · DOI: 10.1016/j.cell.2023.05.047 · Published: July 20, 2023

Simple Explanation

The study investigates the role of internal m7G modification in messenger RNAs (mRNAs). It identifies Quaking proteins (QKIs) as proteins that selectively recognize this modification. QKIs are found to interact with a stress granule (SG) protein and shuttle m7G-modified transcripts into SGs, influencing mRNA stability and translation under stress. Under stress conditions, QKI6 and QKI7 directly interact with the SG core protein G3BP1, colocalize within SGs, shuttle hundreds of internal m7G-modified mRNAs into SGs, and thereby affect mRNA stability and/or translation efficiency. QKI7 sensitizes cancer cells to chemotherapy drugs by suppressing the Hippo signaling pathway via an m7G-dependent mechanism.

Study Duration

Not specified

Participants

HeLa, HepG2, HEK293T, U2OS, THLE-2, SNU475, Hep3B, and SNU449 cell lines, NSG mice

Evidence Level

Not specified

Key Findings

1
QKIs preferentially recognize internal mRNA m7G modifications.
2
QKI7 interacts with the SG core protein G3BP1 only under stress conditions.
3
QKI7 sensitizes cancer cells to chemotherapy drugs (e.g., doxorubicin and sorafenib).

Research Summary

The study identifies Quaking proteins (QKIs) as mRNA internal m7G binding proteins. QKI7 shuttles internal m7G-modified mRNAs into stress granules (SGs) under stress conditions, regulating mRNA metabolism. QKI7 sensitizes cancer cells to chemotherapy drugs, suggesting a therapeutic potential of targeting QKIs.

Practical Implications

Drug development

Targeting QKIs, particularly QKI7, could enhance the effectiveness of chemotherapy drugs in cancer treatment.

Understanding stress response

The study provides insights into how cells respond to stress by modulating mRNA metabolism through QKIs and m7G modification.

Targeted therapies

Modulating the QKI7-m7G axis could offer a targeted approach to overcome drug resistance in various tumors.

Study Limitations

1
Current m7G antibodies cannot distinguish between m7G cap and internal m7G sites, which may lead to unwanted contamination.
2
The abundance of internal m7G modifications is relatively low, which warrants the development of more sensitive and accurate methods to precisely detect it.
3
The underlying mechanism regarding how QKI7 interacts with G3BP1 and responses under stress conditions has yet to be fully characterized.

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