Translational repression of human matrix metalloproteinases-13 by an alternatively spliced form of T-cell-restricted intracellular antigen-related protein (TIAR)

Human matrix metalloproteinases-13 (HMMP13) shows a wide substrate specificity, and its expression is limited to pathological situations such as chronic inflammation and cancer. The coding sequence for HMMP13 is 86% identical to rat matrix metalloproteinases-13 (RMMP13); however, the regulation of HMMP13 and RMMP13 protein synthesis in renal mesangial cells is strikingly different. In human cells there is a discordance between HMMP13 mRNA levels and protein expression. Following IL-1beta or TGF-beta(1) stimulation, HMMP13 mRNA levels increase significantly, whereas the protein expression is absent. This discordance is because of a species-dependent translational repression. In addition to the W-untranslated region of the matrix metalloproteinases-13 (MMP13) gene, the differential expression of an alternatively spliced transcript of the RNA-binding protein TLAR in human cell cultures is also critical for this post-transcriptional regulation. Transient expression of the 17-amino acid insert of the alternatively spliced form of TIAR reverses the HMMP13 mRNA silencing observed in human and primate species. In addition, co-transfection of the alternatively spliced form of TIAR and HMMP13 into Rat2 cells suppresses HMMP13 protein expression. Thus, we report for the first time that a species-dependent TIAR isoform plays a major role in the post-transcriptional silencing for HMMP13.