PubMed:35398356 JSONTXT

{"project":"Inflammaging","denotations":[{"id":"T1","span":{"begin":0,"end":90},"obj":"Sentence"},{"id":"T2","span":{"begin":91,"end":273},"obj":"Sentence"},{"id":"T3","span":{"begin":274,"end":404},"obj":"Sentence"},{"id":"T4","span":{"begin":405,"end":528},"obj":"Sentence"},{"id":"T5","span":{"begin":529,"end":684},"obj":"Sentence"},{"id":"T6","span":{"begin":685,"end":857},"obj":"Sentence"},{"id":"T7","span":{"begin":858,"end":1049},"obj":"Sentence"},{"id":"T8","span":{"begin":1050,"end":1207},"obj":"Sentence"},{"id":"T9","span":{"begin":1208,"end":1339},"obj":"Sentence"},{"id":"T10","span":{"begin":1340,"end":1620},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":90},"obj":"Sentence"},{"id":"T2","span":{"begin":91,"end":273},"obj":"Sentence"},{"id":"T3","span":{"begin":274,"end":404},"obj":"Sentence"},{"id":"T4","span":{"begin":405,"end":528},"obj":"Sentence"},{"id":"T5","span":{"begin":529,"end":684},"obj":"Sentence"},{"id":"T6","span":{"begin":685,"end":857},"obj":"Sentence"},{"id":"T7","span":{"begin":858,"end":1049},"obj":"Sentence"},{"id":"T8","span":{"begin":1050,"end":1207},"obj":"Sentence"},{"id":"T9","span":{"begin":1208,"end":1339},"obj":"Sentence"},{"id":"T10","span":{"begin":1340,"end":1620},"obj":"Sentence"}],"text":"The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo.\nThe 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."}

{"project":"NCBITAXON","denotations":[{"id":"T1","span":{"begin":595,"end":600},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":1231,"end":1235},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"9606"},{"id":"A2","pred":"db_id","subj":"T2","obj":"10088"}],"text":"The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo.\nThe 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."}

{"project":"Anatomy-UBERON","denotations":[{"id":"T1","span":{"begin":240,"end":252},"obj":"Body_part"},{"id":"T2","span":{"begin":1189,"end":1195},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL_0000738"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/CL_0000084"}],"text":"The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo.\nThe 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."}

{"project":"CL-cell","denotations":[{"id":"T1","span":{"begin":240,"end":252},"obj":"Cell"},{"id":"T2","span":{"begin":265,"end":272},"obj":"Cell"},{"id":"T3","span":{"begin":730,"end":737},"obj":"Cell"},{"id":"T4","span":{"begin":1041,"end":1048},"obj":"Cell"},{"id":"T5","span":{"begin":1189,"end":1195},"obj":"Cell"}],"attributes":[{"id":"A1","pred":"cl_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL:0000738"},{"id":"A2","pred":"cl_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/CL:0000084"},{"id":"A3","pred":"cl_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/CL:0000084"},{"id":"A4","pred":"cl_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/CL:0000084"},{"id":"A5","pred":"cl_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/CL:0000084"}],"text":"The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo.\nThe 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."}