ST8SIA4-mediated polysialylation is critical for CCR2-driven monocyte egress from the bone marrow

Polysialylation is a rare post-translational modification critical for brain development and synaptic plasticity. Although also present on circulating leukocytes, its immune functions remain poorly understood. Analysis of human genomic data revealed that natural variants of ST8SIA4, which encodes a key polysialylation enzyme, are associated with reduced circulating monocyte counts. Using St8sia4-deficient mice, we demonstrate that ST8SIA4-dependent polysialylation is essential for CCR2-mediated egress of inflammatory monocytes from bone marrow, both at steady state and during Mycobacterium tuberculosis infection. NCAM1 was confirmed as the primary polysialylated protein in these monocytes, with Ncam1-deficient mice mirroring the monocyte defects seen in St8sia4-deficient animals. Mechanistically, loss of polysialylation triggers cytoskeletal remodeling, alters CCR2 surface organization and disrupts CCR2 ligand engagement and internalization. These findings reveal polysialylation as a previously unrecognized regulator of CCR2 function and monocyte mobilization, with significant implications for immune surveillance and inflammation.