Research ArticleFibrosis

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

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

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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.

Abstract

The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine–rich (SR) protein–mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double-exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis.

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