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

Midgley, Adam C., Oltean, Sebastian, Hascall, Vincent, Woods, Emma L., Steadman, Robert ORCID: https://orcid.org/0000-0002-1303-2496, Phillips, Aled O. ORCID: https://orcid.org/0000-0001-9744-7113 and Meran, Soma ORCID: https://orcid.org/0000-0003-3408-3978 2017. Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype. Science Signaling 10 (506) , eaao1822. 10.1126/scisignal.aao1822

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics
Publisher:	American Association for the Advancement of Science
ISSN:	1945-0877
Funders:	Medical Research Council UK
Date of First Compliant Deposit:	12 December 2017
Date of Acceptance:	4 October 2017
Last Modified:	12 Nov 2024 01:00
URI:	https://orca.cardiff.ac.uk/id/eprint/107003

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