Sumoylation and nuclear translocation of S100A4 regulate IL-1beta-mediated production of matrix metalloproteinase-13.
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.
Miranda
Keally J
KJ
Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Loeser
Richard F
RF
Yammani
Raghunatha R
RR
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D019943:Amino Acid Substitution; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*
D024043:Collagen Type II; C508585:IL1B protein, human; D053583:Interleukin-1beta; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D025842:SUMO-1 Protein; C077591:S100A4 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13