Molecular requirements for sorting of the chemokine interleukin-8/CXCL8 to endothelial Weibel-Palade bodies.
Sorting of proteins to Weibel-Palade bodies (WPB) of endothelial cells allows rapid regulated secretion of leukocyte-recruiting P-selectin and chemokines as well as procoagulant von Willebrand factor (VWF). Here we show by domain swap studies that the exposed aspartic acid in loop 2 (Ser(44)-Asp(45)-Gly(46)) of the CXC chemokine interleukin (IL)-8 is crucial for targeting to WPB. Loop 2 also governs sorting of chemokines to alpha-granules of platelets, but the fingerprint of the loop 2 of these chemokines differs from that of IL-8. On the other hand, loop 2 of IL-8 closely resembles a surface-exposed sequence of the VWF propeptide, the region of VWF that directs sorting of the protein to WPB. We conclude that loop 2 of IL-8 constitutes a critical signal for sorting to WPB and propose a general role for this loop in the sorting of chemokines to compartments of regulated secretion.
Hol
Johanna
J
Institute and University of Oslo, Rikshospitalet University Hospital, Sognsvannsveien 20, 0027 Oslo, Norway.
Küchler
Axel M
AM
Johansen
Finn-Eirik
FE
Dalhus
Bjørn
B
Haraldsen
Guttorm
G
Oynebråten
Inger
I
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016415:Sequence Alignment; D020302:Weibel-Palade Bodies / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016209:Interleukin-8