TY - JOUR
T1 - Regulated intramembrane proteolysis of the interleukin-1 receptor II by α-, β-, and γ-secretase
AU - Kuhn, Peer Hendrik
AU - Marjaux, Els
AU - Imhof, Axel
AU - De Strooper, Bart
AU - Haass, Christian
AU - Lichtenthaler, Stefan F.
PY - 2007/4/20
Y1 - 2007/4/20
N2 - Ectodomain shedding and intramembrane proteolysis of the amyloid precursor protein (APP) by α-, β- and γ-secretase are involved in the pathogenesis of Alzheimer disease (AD). Increased proteolytic processing and secretion of another membrane protein, the interleukin-1 receptor II (IL-1R2), have also been linked to the pathogenesis of AD. IL-1R2 is a decoy receptor that may limit detrimental effects of IL-1 in the brain. At present, the proteolytic processing of IL-1R2 remains little understood. Here we show that IL-1R2 can be proteolytically processed in a manner similar to APP. IL-1R2 expressed in human embryonic kidney 293 cells first undergoes ectodomain shedding in an α-secretase-like manner, resulting in secretion of the IL-1R2 ectodomain and the generation of an IL-1R2 C-terminal fragment. This fragment undergoes further intramembrane proteolysis by γ-secretase, leading to the generation of the soluble intracellular domain of IL-1R2. Intramembrane cleavage of IL-1R2 was abolished by a highly specific inhibitor of γ-secretase and was absent in mouse embryonic fibroblasts deficient in γ-secretase activity. Surprisingly, the β-secretase BACE1 and its homolog BACE2 increased IL-1R2 secretion resulting in C-terminal fragments nearly identical to the ones generated by the α-secretase-like cleavage. This suggests that both proteases may act as alternative α-secretase-like proteases. Importantly, BACE1 and BACE2 did not cleave several other membrane proteins, demonstrating that both proteases do not contribute to general membrane protein turnover but only cleave specific proteins. This study reveals a similar proteolytic processing of IL-1R2 and APP and may provide an explanation for the increased IL-1R2 secretion observed in AD.
AB - Ectodomain shedding and intramembrane proteolysis of the amyloid precursor protein (APP) by α-, β- and γ-secretase are involved in the pathogenesis of Alzheimer disease (AD). Increased proteolytic processing and secretion of another membrane protein, the interleukin-1 receptor II (IL-1R2), have also been linked to the pathogenesis of AD. IL-1R2 is a decoy receptor that may limit detrimental effects of IL-1 in the brain. At present, the proteolytic processing of IL-1R2 remains little understood. Here we show that IL-1R2 can be proteolytically processed in a manner similar to APP. IL-1R2 expressed in human embryonic kidney 293 cells first undergoes ectodomain shedding in an α-secretase-like manner, resulting in secretion of the IL-1R2 ectodomain and the generation of an IL-1R2 C-terminal fragment. This fragment undergoes further intramembrane proteolysis by γ-secretase, leading to the generation of the soluble intracellular domain of IL-1R2. Intramembrane cleavage of IL-1R2 was abolished by a highly specific inhibitor of γ-secretase and was absent in mouse embryonic fibroblasts deficient in γ-secretase activity. Surprisingly, the β-secretase BACE1 and its homolog BACE2 increased IL-1R2 secretion resulting in C-terminal fragments nearly identical to the ones generated by the α-secretase-like cleavage. This suggests that both proteases may act as alternative α-secretase-like proteases. Importantly, BACE1 and BACE2 did not cleave several other membrane proteins, demonstrating that both proteases do not contribute to general membrane protein turnover but only cleave specific proteins. This study reveals a similar proteolytic processing of IL-1R2 and APP and may provide an explanation for the increased IL-1R2 secretion observed in AD.
UR - http://www.scopus.com/inward/record.url?scp=34249730581&partnerID=8YFLogxK
U2 - 10.1074/jbc.M700356200
DO - 10.1074/jbc.M700356200
M3 - Article
C2 - 17307738
AN - SCOPUS:34249730581
SN - 0021-9258
VL - 282
SP - 11982
EP - 11995
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -