Abstract
S100A4, a member of the S100 family of proteins, plays an important role in matrix remodeling by up-regulating the expression of matrix metalloproteinases (MMPs). We have previously shown that S100A4 is overexpressed in diseased cartilage and that extracellular S100A4 stimulates MMP-13 production, a major type II collagen-degrading enzyme, via activation of receptor for advanced glycation end product signaling. In the present study, using human articular chondrocytes, we show that intracellular S100A4 translocated into the nucleus upon interleukin-1β (IL-1β) stimulation and translocation required post-translational modification of S100A4 by the sumo-1 protein. Two sumoylation sites were identified on the S100A4 molecule, Lys(22) and Lys(96). Mutation of these lysine residues abolished the ability of S100A4 to be sumoylated and to translocate into the nucleus. Blocking of sumoylation and nuclear transport of S100A4 inhibited the IL-1β-induced production of MMP-13. Nuclear S100A4 was bound to the promoter region of MMP-13 in IL-1β-treated cells. Thus, we demonstrate a novel mechanism for sumoylated S100A4 as a regulator of expression of the MMP-13 gene.
Highlights
S100A4 was originally isolated as a gene that was differentially expressed in mouse adenocarcinoma cells [9] and subsequently found in other tissues [10, 11]
We demonstrate that treatment of chondrocytes with IL-1 promotes nuclear translocation of S100A4, which required the post-translational modification of sumoylation
These results suggest that a portion of the cytosolic S100A4 translocates into the nucleus upon IL-1 stimulation in chondrocytes
Summary
S100A4 was originally isolated as a gene that was differentially expressed in mouse adenocarcinoma cells [9] and subsequently found in other tissues [10, 11]. We demonstrate that treatment of chondrocytes with IL-1 promotes nuclear translocation of S100A4, which required the post-translational modification of sumoylation. Cells were treated with IL-1 for 0 – 60 min and total cell extracts (250 g of protein) were immunoprecipitated with anti-sumo-1 antibody followed by immunoblotting with anti-S100A4 (Fig. 2A).
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