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| Item Type: | Preprint |
|---|---|
| Title: | Human ADA2 deficiency is characterized by the absence of an intracellular hypoglycosylated form of adenosine deaminase 2 |
| Creators Name: | Ehlers, L., Hombrouck, A., Wouters, M., Pillay, B., Delafontaine, S., Bucciol, G., Baggio, M., Dzhus, M., Ebstein, F., Jacquemyn, M., De Somer, L., Schrijvers, R., Vanderschueren, S., Cassiman, D., Kirchner, M., Mertins, P., Mashreghi, M.F., Kallinich, T., Daelemans, D., Agostinis, P., Moens, L. and Meyts, I. |
| Abstract: | Human deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease with a complex clinical phenotype of recurrent fever, vasculitis and stroke as well as immunodeficiency and bone marrow failure. It is caused by pathogenic variants in ADA2 that lead to impaired ADA2 protein secretion and reduced deaminase activity. However, the mechanisms driving the disease on a cellular level remain elusive. Here, we analyze protein expression of mutant ADA2 in human monocyte-derived macrophages from 10 DADA2 patients. We identify a low-molecular-weight (LMW) form of ADA2 expressed exclusively intracellularly in healthy control macrophages. This LMW-ADA2 is subject to glycan trimming by α-mannosidases after transfer to the Golgi and is distinct from secreted highmolecular-weight (HMW) ADA2. DADA2 patients’ monocyte-derived macrophages lack LMWADA2 and mutant ADA2 does not undergo glycan processing in the Golgi. We confirm the absence of LMW-ADA2 upon overexpression of 11 pathogenic ADA2 variants in HEK293T cells and monocytic U-937 cells. By subcellular fractionation, we show that LMW-ADA2 localizes to the cytosolic and lysosomal compartments. In conclusion, we describe a previously unreported intracellular hypoglycosylated form of ADA2 and establish the absence of this LMW-ADA2 as a cellular characteristic of DADA2. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2023.10.25.564037v3 |
| Date: | 8 October 2024 |
| Official Publication: | https://doi.org/10.1101/2023.10.25.564037 |
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