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Structural basis for inflammation-driven shedding of CD163 ectodomain and tumor necrosis factor-α in macrophages

Structural basis for inflammation-driven shedding of CD163 ectodomain and tumor necrosis factor-α in macrophages
Structural basis for inflammation-driven shedding of CD163 ectodomain and tumor necrosis factor-α in macrophages
The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. 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 ((1044)Arg-Ser-Ser-Arg) and proTNF-α ((78)Arg-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 ADAM17 stimulation. This was further evidenced by analysis of mouse CD163 that, like CD163 in other non-primates, does not contain the palindromic 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 with that of human CD163. In conclusion, we have identified an essential substrate motif for ADAM17-mediated CD163 and proTNF-α cleavage in macrophages. In addition, the present data indicate that CD163, by incorporation of this motif in late evolution, underwent a modification that allows for an instant down-regulation 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
0021-9258
778-788
Etzerodt, Anders
8d57037c-2cd9-4607-be3a-3b95716c36e0
Rasmussen, Mie Rostved
807c24f9-759c-4add-9de5-e43aa0212476
Svendsen, Pia
40b69eb0-d343-4c80-9e51-eff7a5e1f881
Chalaris, Athena
2b942a79-3946-4981-a14b-d507fd11ca54
Schwarz, Jeanette
f52b8f23-353e-46f4-811e-1f4a7c3b49f4
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Møller, Holger Jon
6454a13e-aab9-4fb4-bd29-58ae31c4ae04
Moestrup, Søren Kragh
059d0e51-7f48-4aa5-9543-9a493b38ab5c
Etzerodt, Anders
8d57037c-2cd9-4607-be3a-3b95716c36e0
Rasmussen, Mie Rostved
807c24f9-759c-4add-9de5-e43aa0212476
Svendsen, Pia
40b69eb0-d343-4c80-9e51-eff7a5e1f881
Chalaris, Athena
2b942a79-3946-4981-a14b-d507fd11ca54
Schwarz, Jeanette
f52b8f23-353e-46f4-811e-1f4a7c3b49f4
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Møller, Holger Jon
6454a13e-aab9-4fb4-bd29-58ae31c4ae04
Moestrup, Søren Kragh
059d0e51-7f48-4aa5-9543-9a493b38ab5c

Etzerodt, Anders, Rasmussen, Mie Rostved, Svendsen, Pia, Chalaris, Athena, Schwarz, Jeanette, Galea, Ian, Møller, Holger Jon and Moestrup, Søren Kragh (2014) Structural basis for inflammation-driven shedding of CD163 ectodomain and tumor necrosis factor-α in macrophages. The Journal of Biological Chemistry, 289 (2), 778-788. (doi:10.1074/jbc.M113.520213). (PMID:24275664)

Record type: Article

Abstract

The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. 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 ((1044)Arg-Ser-Ser-Arg) and proTNF-α ((78)Arg-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 ADAM17 stimulation. This was further evidenced by analysis of mouse CD163 that, like CD163 in other non-primates, does not contain the palindromic 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 with that of human CD163. In conclusion, we have identified an essential substrate motif for ADAM17-mediated CD163 and proTNF-α cleavage in macrophages. In addition, the present data indicate that CD163, by incorporation of this motif in late evolution, underwent a modification that allows for an instant down-regulation 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

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Published date: 10 January 2014
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 384274
URI: https://eprints.soton.ac.uk/id/eprint/384274
ISSN: 0021-9258
PURE UUID: 35912c88-b932-4f40-a4dd-a9114e26329b
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

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Date deposited: 30 Nov 2015 09:27
Last modified: 06 Jun 2018 12:46

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