The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo.
ADAM10
CD25
IL-2Rα
T-cell biology
interleukin-2
protease
shedding
signaling
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
04
11
2021
revised:
04
04
2022
accepted:
05
04
2022
pubmed:
11
4
2022
medline:
30
6
2022
entrez:
10
4
2022
Statut:
ppublish
Résumé
The cytokine interleukin-2 (IL-2) plays a critical role in controlling the immune homeostasis by regulating the proliferation and differentiation of immune cells, especially T cells. IL-2 signaling is mediated via the IL-2 receptor (IL-2R) complex, which consists of the IL-2Rα (CD25), the IL-2Rβ, and the IL-2Rγ. While the latter are required for signal transduction, IL-2Rα controls the ligand-binding affinity of the receptor complex. A soluble form of the IL-2Rα (sIL-2Rα) is found constitutively in human serum, though its levels are increased under various pathophysiological conditions. The sIL-2Rα originates partly from activated T cells through proteolytic cleavage, but neither the responsible proteases nor stimuli that lead to IL-2Rα cleavage are known. Here, we show that the metalloproteases ADAM10 and ADAM17 can cleave the IL-2Rα and generate a soluble ectodomain, which functions as a decoy receptor that inhibits IL-2 signaling in T cells. We demonstrate that ADAM10 is mainly responsible for constitutive shedding of the IL-2Rα, while ADAM17 is involved in IL-2Rα cleavage upon T cell activation. In vivo, we found that mice with a CD4-specific deletion of ADAM10, but not ADAM17, show reduced steady-state sIL-2Rα serum levels. We propose that the identification of proteases involved in sIL-2Rα generation will allow for manipulation of IL-2Rα cleavage, especially as constitutive and induced cleavage of IL-2Rα are executed by different proteases, and thus offer a novel opportunity to alter IL-2 function.
Identifiants
pubmed: 35398356
pii: S0021-9258(22)00350-7
doi: 10.1016/j.jbc.2022.101910
pmc: PMC9127578
pii:
doi:
Substances chimiques
Interleukin-2
0
Interleukin-2 Receptor alpha Subunit
0
Receptors, Interleukin-2
0
ADAM10 Protein
EC 3.4.24.81
Adam10 protein, mouse
EC 3.4.24.81
ADAM17 Protein
EC 3.4.24.86
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101910Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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