Research ArticleFibrosis

Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype

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Science Signaling  21 Nov 2017:
Vol. 10, Issue 506, eaao1822
DOI: 10.1126/scisignal.aao1822

A nuclear function for hyaluronidase 2

Alternative splicing produces distinct isoforms of the cell surface protein CD44. Whereas the standard isoform [standard CD44 (CD44s)] is associated with the differentiation of the myofibroblasts that drive fibrosis, the CD44v7/8 isoform is associated with the prevention and reversal of myofibroblast differentiation. CD44 acts as a receptor for various ligands, including the extracellular matrix component hyaluronan. Midgley et al. found that hyaluronidase 2 (HYAL2), an enzyme that degrades hyaluronan, promoted the production of CD44v7/8 through a mechanism that appeared to be independent of its enzymatic activity. When primary human lung fibroblasts were stimulated with bone morphogenetic protein 7 (BMP7), which prevents the differentiation of myofibroblasts, HYAL2 translocated to the nucleus. HYAL2 displaced components of the splicing machinery on CD44 pre–messenger RNA (mRNA), thus preventing the splicing events that generate CD44s mRNA and promoting the production of CD44v7/8 mRNA. These findings identify a potentially important switch in fibrosis and a nuclear role for HYAL2.

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