Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases

• DOI: 10.3389/fimmu.2021.701739
• Publication Date: 2021-06-30T06:15:36Z
• Authors: Jennifer Vandooren; Rafaela Vaz Sousa...; Estefania Ugarte-...; Vasily Rybakin; Sam Noppen; Melissa R. Stas; Eline Bernaerts; Eva Ganseman; Mieke Metzemaekers; Dominique Schols; Paul Proost; Ghislain Opdenakker
• Keywords: Neutrophil elastase

Interleukin 7 (IL-7) is a cell growth factor with central role in normal T development, survival and differentiation. The lack of IL-7–IL-7 receptor(R)-mediated signaling compromises lymphoid whereas increased activity contributes to the development chronic inflammation, cancer autoimmunity. Gain-of-function alterations IL-7R through Janus kinases (JAKs) signal transducers activators transcription (STATs) are enriched acute lymphoblastic leukemia (T-ALL) autocrine production IL-7 by T-ALL cells involved phenotypes leukemic initiation oncogenic spreading. Several IL-7-associated pathologies also characterized presence matrix metalloproteinase-9 (MMP-9), due neutrophil degranulation its regulated other types. Since proteases secreted neutrophils known modulate many cytokines, we investigated interactions between IL-7, MMP-9 several neutrophil-derived proteases. We demonstrated that efficiently cleaved human exposed loop α-helices C D this process delayed N-linked glycosylation. Functionally, proteolytic cleavage did not influence IL-7Rα binding internalization nor direct pro-proliferative effects on line (HPB-ALL) or primary CD8 + peripheral blood mononuclear cells. A comparable effect was observed for serine elastase, proteinase 3 combinations Hence, glycosylation disulfide bonding as two posttranslational modifications bioavailability species: protects against proteolysis, internal cysteine bridging under physiological redox state keeps conformations active proteoforms. Finally, showed mouse does contain protease-sensitive and, consequently, MMP-9. With latter finding discovered differences biology species.