Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding.
Proteolytic cleavage of the extracellular domain of the type II IL-1 decoy receptor (IL-1RII) generates soluble IL-1-binding proteins that prevent excessive bioactivity by binding free IL-1. In this study we report that an aminopeptidase, aminopeptidase regulator of TNFR1 shedding (ARTS-1), is required for IL-1RII shedding. Coimmunoprecipitation experiments demonstrate an association between endogenous membrane-associated ARTS-1 and a 47-kDa IL-1RII, consistent with ectodomain cleavage of the membrane-bound receptor. A direct correlation exists between ARTS-1 protein expression and IL-1RII shedding, as cell lines overexpressing ARTS-1 have increased IL-1RII shedding and decreased membrane-associated IL-1RII. Basal IL-1RII shedding is absent from ARTS-1 knockout cell lines, demonstrating that ARTS-1 is required for constitutive IL-1RII shedding. Similarly, PMA-mediated IL-1RII shedding is almost entirely ARTS-1-dependent. ARTS-1 expression also enhances ionomycin-induced IL-1RII shedding. ARTS-1 did not alter levels of membrane-associated IL-1RI or IL-1R antagonist release from ARTS-1 cell lines, which suggests that the ability of ARTS-1 to promote shedding of IL-1R family members may be specific for IL-1RII. Further, increased IL-1RII shedding by ARTS-1-overexpressing cells attenuates the biological activity of IL-1beta. We conclude that the ability of ARTS-1 to enhance IL-1RII shedding represents a new mechanism by which IL-1-induced cellular events can be modulated. As ARTS-1 also promotes the shedding of the structurally unrelated 55-kDa, type I TNF receptor and the IL-6R, we propose that ARTS-1 may play an important role in regulating innate immune and inflammatory responses by increasing cytokine receptor shedding.
Cui
Xinle
X
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
Rouhani
Farshid N
FN
Hawari
Feras
F
Levine
Stewart J
SJ
D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020134:Catalytic Domain / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D058851:GPI-Linked Proteins; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D008666:Metalloendopeptidases; D045726:Metalloproteases / Q000172:deficiency / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016254:Mutagenesis, Insertional; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors
D015703:Antigens, CD; D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D008074:Lipoproteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; D020033:Protein Isoforms; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D047888:Receptors, Tumor Necrosis Factor, Type I; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D045726:Metalloproteases; D000626:Aminopeptidases; C464841:ERAP1 protein, human; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human; D002118:Calcium