Structural Basis for Inflammation-driven Shedding of CD163 Ectodomain and Tumor Necrosis Factor-α in Macrophages

摘要: The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. This leads release of soluble (sCD163) bioactive TNF-α. Sequence comparison juxtamembrane region identified similar palindromic sequences in human (1044Arg-Ser-Ser-Arg) (78Arg-Ser-Ser-Ser-Arg). In Arg-Ser-Ser-Ser-Arg sequence is situated next previously established ADAM17 site. Site-directed mutagenesis revealed that harbor essential information for efficient two upon stimulation. was further evidenced analysis mouse that, like other non-primates, does not contain region. Mouse resisted endotoxin- phorbol ester-induced shedding, ex vivo knock-in Arg-Ser-Ser-Arg a shedding comparable with CD163. conclusion, we have an substrate motif ADAM17-mediated macrophages. addition, present data indicate CD163, incorporation this late evolution, underwent modification allows instant down-regulation surface expression inhibition hemoglobin uptake. regulatory modality seems coincided evolution enhanced hemoglobin-protecting role haptoglobin-CD163 system primates.