Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes

The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and charac-terize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heter-ologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.

Automated summary

This study discovered two novel genetic defects in SRPRA and SRP19 genes, which are involved in the differentiation of neutrophil granulocytes. Proteome analysis of neutrophil granulocytes from patients with variants in SRP genes revealed global and specific proteome aberrations. In vitro and in vivo experiments confirmed the crucial role of SRP-dependent protein processing, intracellular trafficking, and homeostasis in neutrophil granulocyte differentiation.