Menin is a scaffold protein encoded by the Men1 gene, and it interacts with a variety of chromatin regulators to activate or repress cellular processes. The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) through inactivation of the granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with the SET domain containing 2 (SETD2) through the N-terminal domain (NTD) and Palm domains to maintain protein stability and chromatin recruitment. SETD2 and menin collectively maintain CSF2 expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis. Targeting H3K36me3 remodeling mitigated the aberrant activation of macrophages caused by lipopolysaccharide (LPS). Our results point to a nonredundant role of menin in the control of macrophage lineage maintenance via reinforcement of the H3K36me3 transcriptional program.
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