BRD3 PROTAC分解剤はH3K18acを標的とし、網膜ミクログリア駆動性ぶどう膜炎を軽減する

関連する実験動画

Updated: Jan 27, 2026

Generation of Human Microglia to Combine Them with Retinal Organoids for Improved Disease Modeling

Generation of Human Microglia to Combine Them with Retinal Organoids for Improved Disease Modeling

Published on: July 26, 2024

Zhi Zhang^1,2,3, Tianlong Lan⁴, Yongbo Liu⁴

¹Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

|January 26, 2026

Abstract:

Uveitis is a sight-threatening intraocular inflammation in which the proinflammatory immune response driven by retinal microglia is a key contributor. Proteolysis targeting chimera (PROTAC) targeting bromodomain and extraterminal (BET) proteins has shown therapeutic effects in certain inflammatory diseases or tumors, but their effects on uveitis remain elusive. Our research demonstrated that PROTAC D072 reduced intraocular inflammation in vivo and inhibited proinflammatory microglia in both uveitis retina and lipopolysaccharide (LPS) treated mouse microglia cell line BV2. Drug target verification revealed that D072 specifically degraded BRD3 but did not significantly affect BRD2 or BRD4. Mechanistically, BRD3 degradation resulted in reduced H3K18ac, and CUT&Tag analysis revealed changes in the occupancy of several proinflammatory and metabolism-related genes. Furthermore, histone deacetylases (HDACs) partially regulate the H3K18ac level following BRD3 degradation. Overall, we identified D072 as a specific degrader of BRD3 in the murine system that can inhibit proinflammatory microglia in autoimmune uveitis, potentially providing a therapeutic approach for uveitis.

キーワード:

生物科学エピジェネティクス眼科学

さらに関連する動画

Primed Mycobacterial Uveitis PMU as a Model for Post-Infectious Uveitis

Primed Mycobacterial Uveitis PMU as a Model for Post-Infectious Uveitis

Published on: December 17, 2021

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

関連する概念動画

Regulated Protein Degradation

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...

Regulated Protein Degradation

Regulated Protein Degradation

Proteins: From Genes to Degradation

Proteins: From Genes to Degradation

Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick. Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA...

Proteins: From Genes to Degradation

Proteins: From Genes to Degradation

ATP Driven Pumps I: An Overview

ATP Driven Pumps I: An Overview

ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and...

Role of Matrix Metalloproteases in Degradation of ECM

Role of Matrix Metalloproteases in Degradation of ECM

Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult...