A single protein acts as a memory gatekeeper that keeps the immune system on high alert long after a threat has vanished.
Innate immunity was once thought to be a simple, short-lived response system without a memory. The protein Setdb2 silences specific metabolic genes to keep immune cells in a trained and ready state. This epigenetic lock ensures the body stays primed to fight off future infections more effectively. Without this gatekeeper, the immune system loses its memory and becomes vulnerable to repeat attacks. Controlling this mechanism could lead to new ways to boost vaccine effectiveness or treat chronic inflammatory diseases.
Setdb2 Silences HIF-2α to Sustain the HIF-1α Metabolic Program in Trained Immunity
research_square · rs-9391910
Abstract β-glucan-induced trained immunity requires sustained mTOR–HIF-1α signaling, yet how this metabolic program persists for days after the initial stimulus is removed remains unclear. Here, we show that the H3K9 methyltransferase Setdb2 resolves this question by selectively silencing HIF-2α ( Epas1 ) and multiple anti-inflammatory brake genes during the memory phase. In β-glucan-trained wild-type macrophages, the HIF-1α/HIF-2α mRNA ratio is 3-fold higher than in Setdb2 -deficient macrophage