BRD3 PROTAC degrader targets H3K18ac to alleviate retinal microglia-driven uveitis
Zhi Zhang, Tianlong Lan, Yongbo Liu, Hui Yang, Nan Shu, Ruonan Li, Wanqian Li, Qian Zhou, Peizeng Yang, Yu Rao, Shengping Hou
TL;DR
A PROTAC called D072 reduces inflammation in retinal microglia by degrading BRD3, potentially offering a new treatment for uveitis.
Contribution
D072 is a specific BRD3 degrader that alleviates uveitis by modulating H3K18ac and proinflammatory gene activity.
Findings
PROTAC D072 reduces intraocular inflammation and inhibits proinflammatory microglia in uveitis.
BRD3 degradation by D072 leads to reduced H3K18ac and altered chromatin states of inflammation-related genes.
HDACs partially regulate H3K18ac levels following BRD3 degradation, affecting CCL5 signaling.
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…
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Taxonomy
TopicsOcular Diseases and Behçet’s Syndrome · Protein Degradation and Inhibitors · Retinal Diseases and Treatments