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The TRIM33 Bromodomain Recognizes Histone Lysine Lactylation
Raymundo Nuñez1, Paul F W Sidlowski1, Erica A Steen1
1Department of Biochemistry, Program in Chemical Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
ACS Chemical Biology
|November 18, 2024
Summary
Researchers discovered TRIM33 binds to histone lysine lactylation (Kla), a modification regulating macrophage polarization. This finding links Kla to inflammatory gene expression and macrophage function, identifying TRIM33 as a key protein reader.
Area of Science:
- Epigenetics and Molecular Biology
- Immunology and Cell Biology
Background:
- Histone lysine lactylation (Kla) regulates inflammatory gene expression and macrophage polarization.
- The molecular mechanisms and protein readers of Kla are largely unknown.
Purpose of the Study:
- To identify bromodomain-containing proteins that bind histone Kla.
- To elucidate the molecular mechanisms and structural basis of Kla recognition by TRIM33.
Main Methods:
- Screening of 28 bromodomains for binding to Kla peptides using AlphaScreen assays.
- Confirmation of binding affinity using isothermal titration calorimetry and protein-detected nuclear magnetic resonance.
- Structural analysis including sequence alignment, molecular modeling, and site-directed mutagenesis.
Main Results:
- TRIM33 was the only bromodomain identified that binds to histone Kla peptides.
- TRIM33 bromodomain exhibits submicromolar binding affinity for both Kla and lysine acetylation (Kac).
- A unique glutamic acid residue in TRIM33 confers specificity for Kla binding.
Conclusions:
- TRIM33 is identified as a novel reader of histone Kla.
- TRIM33 may bridge the gap between histone Kla and macrophage polarization.
- This study provides structural and biophysical insights into Kla recognition and its role in inflammation.
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