Søren Kragh Moestrup

Structural Basis for inflammation-Driven Shedding of CD163 and Tumor Necrosis Factor-α in Macrophages

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The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease AD-AM17. This leads to release of soluble CD163 (sCD163) and bioactive TNF-α. Sequence comparison of the juxtamembrane region identified similar palindromic sequences in human CD163 (1044Arg-Ser-Ser-Arg) and proTNF-α (78Arg-Ser-Ser-Ser-Arg). In proTNF-α the Arg-Ser-Ser-Ser-Arg sequence is situated next to the previously established ADAM17 cleavage site. Site-directed mutagenesis revealed that the sequences harbor essential information for efficient cleavage of the two proteins upon AD-AM17 stimulation. This was further evidenced by analysis of mouse CD163 that, like CD163 in other non-primates, does not contain the palin-dromic CD163 sequence in the juxtamembrane region. Mouse CD163 resisted endotoxin and phorbol ester-induced shedding and ex-vivo analysis of knock-in of the Arg-Ser-Ser-Arg sequence in mouse CD163 revealed a receptor shedding comparable to that of human CD163. In conclusion, we have identified an es-sential substrate motif for ADAM17-mediated CD163 and proTNF-α cleavage in macrophag-es. In addition, the present data indicate that CD163, by incorporation of this motif in late evolution, undervent a modification that allows for an instant downregulation of surface CD163 expression and inhibition of hemoglobin uptake. This regulatory modality seems to have coincided with the evolution of an enhanced hemoglobin-protecting role of the haptoglobin-CD163 system in primates.
Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)778-788
Number of pages11
Publication statusPublished - 10 Jan 2014

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