Jagunal homolog 1 safeguards neutrophil immune function by preserving protein sialylation during differentiation.

Neutrophils are the most abundant circulating leukocytes in humans and act as key effectors of innate immunity. Severe congenital neutropenia (SCN) encompasses a heterogeneous group of disorders characterized by early onset of recurrent infections. Mutations in Jagunal homolog 1 (Jagn1) cause SCN, yet the mechanisms linking Jagn1 deficiency to defective neutrophil function and neutropenia remain unclear. Here, we identify Jagn1 as a critical regulator that connects intracellular protein trafficking and surface glycosylation during neutrophil development. Using neutrophils derived from Hoxb8-ER-immortalized progenitors, we show that Jagn1 expression is restricted to early progenitor stages and transcriptionally controlled by the transcription factor C/EBP-α. Loss of Jagn1 delays neutrophil differentiation, resulting in progenitor accumulation. Functionally, Jagn1-deficient murine neutrophils exhibit defective E-selectin-dependent rolling and chemokine-induced adhesion in ex vivo and in vitro flow chambers, mirrored by impaired rolling, adhesion and transmigration in vivo during TNF-induced inflammation. Mechanistically, lectin-binding and static adhesion assays revealed reduced sialylation of adhesion-relevant receptors on Jagn1-deficient neutrophils leading to impaired E-selectin and CXCL8 binding. In addition, NLRP3-dependent S100A8/A9 release from Jagn1-deficient neutrophils was reduced upon E-selectin stimulation. These findings define Jagn1 as a key determinant of neutrophil protein sialylation through regulating ER-Golgi posttranslational glycosylation, ensuring proper sialylation of adhesion relevant molecules including E-selectin ligands and CXCR2. This mechanism provides a unifying explanation for the clinical and cellular phenotype in Jagn1-associated SCN, which might offer new therapeutic approaches in the treatment of patients with loss of function mutation of Jagn1.