{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:31:02Z","timestamp":1786516262355,"version":"build-2736575974"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>\n                    Hyaluronan (HA) is a major glycosaminoglycan of the extracellular matrix that regulates cell migration, signaling, and tissue homeostasis. Its turnover is controlled by coordinated synthesis by HA synthases and degradation by hyaluronidases. Among these hyaluronidases, TMEM2, the only known transmembrane hyaluronidase, plays a unique role in HA degradation at the cell surface; however, the cellular conditions that support its activity remain incompletely understood. To address this, we developed a cell-based HA turnover assay to examine TMEM2-mediated degradation of endogenously synthesized HA, rather than exogenously added, fluorescently labeled HA used in previous studies. Using this system, we show that TMEM2 readily degrades high-molecular weight HA synthesized by co-expressed HAS3. This degradation occurs only when TMEM2 and HAS3 are co-expressed in the same cells (\n                    <jats:italic>cis<\/jats:italic>\n                    ), whereas co-culture of TMEM2-expressing cells with HAS3-expressing cells supports little or no degradation. Interestingly, HA-binding cell surface receptors CD44 and its homolog LYVE-1 promote efficient TMEM2-mediated HA degradation even under\n                    <jats:italic>trans<\/jats:italic>\n                    conditions, whereas other HA-binding proteins, including TSG-6, layilin, TLR2, RHAMM, and ICAM-1, do not. These findings suggest a spatially regulated mechanism of TMEM2 activity in which capture of HA at the cell surface, mediated by CD44 or LYVE-1, contributes to efficient HA degradation by TMEM2.\n                  <\/jats:p>","DOI":"10.3389\/fmolb.2026.1852012","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:56:36Z","timestamp":1786514196000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Regulation of TMEM2-mediated hyaluronan degradation by CD44 and LYVE-1"],"prefix":"10.3389","volume":"13","author":[{"given":"Yuki","family":"Tobisawa","sequence":"first","affiliation":[{"name":"Department of Urology, Gifu University Hospital","place":["Gifu, Japan"]},{"name":"Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced Study, Gifu University","place":["Gifu, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiakira","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Urology, Gifu University Hospital","place":["Gifu, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Tomioka-Inagawa","sequence":"additional","affiliation":[{"name":"Department of Urology, Gifu University Hospital","place":["Gifu, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitoshi","family":"Irie","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Koie","sequence":"additional","affiliation":[{"name":"Department of Urology, Gifu University Hospital","place":["Gifu, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1083\/jcb.144.4.789","article-title":"LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan","volume":"144","author":"Banerji","year":"1999","journal-title":"J. Cell Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2754","DOI":"10.1038\/s41467-025-57866-8","article-title":"Structure and unusual binding mechanism of the hyaluronan receptor LYVE-1 mediating leucocyte entry to lymphatics","volume":"16","author":"Bano","year":"2025","journal-title":"Nat. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1091\/mbc.12.4.891","article-title":"Layilin, a novel integral membrane protein, is a hyaluronan receptor","volume":"12","author":"Bono","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"B4","first-page":"41","article-title":"Turnover and metabolism of hyaluronan","volume":"143","author":"Fraser","year":"1989","journal-title":"Ciba Found. Symp."},{"key":"B5","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.cell.2017.12.023","article-title":"Transmembrane pickets connect Cyto- and pericellular skeletons forming barriers to receptor engagement","volume":"172","author":"Freeman","year":"2018","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1083\/jcb.117.6.1343","article-title":"Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility","volume":"117","author":"Hardwick","year":"1992","journal-title":"J. Cell Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1009765","DOI":"10.1371\/journal.pgen.1009765","article-title":"The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival","volume":"18","author":"Inubushi","year":"2022","journal-title":"PLoS Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"100481","DOI":"10.1016\/j.jbc.2021.100481","article-title":"The cell surface hyaluronidase TMEM2 regulates cell adhesion and migration via degradation of hyaluronan at focal adhesion sites","volume":"296","author":"Irie","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1146\/annurev.cellbio.23.090506.123337","article-title":"Hyaluronan in tissue injury and repair","volume":"23","author":"Jiang","year":"2007","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e202000908","DOI":"10.26508\/lsa.202000908","article-title":"Dendritic cell entry to lymphatic capillaries is orchestrated by CD44 and the hyaluronan glycocalyx","volume":"4","author":"Johnson","year":"2021","journal-title":"Life Sci. Alliance"},{"key":"B11","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1083\/jcb.116.2.545","article-title":"A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44","volume":"116","author":"Lee","year":"1992","journal-title":"J. Cell Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"22466","DOI":"10.1074\/jbc.273.35.22466","article-title":"HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity","volume":"273","author":"Lepperdinger","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"26967","DOI":"10.1074\/jbc.M002527200","article-title":"Hyaluronan binding by cell surface CD44","volume":"275","author":"Lesley","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2671","DOI":"10.1016\/j.bpj.2022.06.021","article-title":"Molecular mechanism of CD44 homodimerization modulated by palmitoylation and membrane environments","volume":"121","author":"Ma","year":"2022","journal-title":"Biophys. J."},{"key":"B15","doi-asserted-by":"crossref","first-page":"30081","DOI":"10.1016\/S0021-9258(18)43775-1","article-title":"Intercellular adhesion molecule-1 is a cell surface receptor for hyaluronan","volume":"269","author":"McCourt","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1177\/00220345231182355","article-title":"Tmem2 deficiency leads to enamel hypoplasia and soft enamel in mouse","volume":"102","author":"Nag","year":"2023","journal-title":"J. Dent. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"105120","DOI":"10.1016\/j.jbc.2023.105120","article-title":"TMEM2 is a bona fide hyaluronidase possessing intrinsic catalytic activity","volume":"299","author":"Narita","year":"2023","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"104826","DOI":"10.1016\/j.jbc.2023.104826","article-title":"Human TMEM2 is not a catalytic hyaluronidase, but a regulator of hyaluronan metabolism via HYBID (KIAA1199\/CEMIP) and HAS2 expression","volume":"299","author":"Sato","year":"2023","journal-title":"J. Biol. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1021\/cr050247k","article-title":"Hyaluronidases: their genomics, structures, and mechanisms of action","volume":"106","author":"Stern","year":"2006","journal-title":"Chem. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"28878","DOI":"10.1074\/jbc.273.44.28878","article-title":"Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides","volume":"273","author":"Tammi","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"101281","DOI":"10.1016\/j.jbc.2021.101281","article-title":"The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover","volume":"297","author":"Tobisawa","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"6296","DOI":"10.1073\/pnas.96.11.6296","article-title":"Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX","volume":"96","author":"Triggs-Raine","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/pgr2.70021","article-title":"TMEM2: a new dimension in hyaluronan biology","volume":"3","author":"Yamaguchi","year":"2025","journal-title":"Proteoglycan Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"7304","DOI":"10.1074\/jbc.M116.770149","article-title":"A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase","volume":"292","author":"Yamamoto","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"5612","DOI":"10.1073\/pnas.1215432110","article-title":"KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization","volume":"110","author":"Yoshida","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1852012\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:56:36Z","timestamp":1786514196000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1852012\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":25,"alternative-id":["10.3389\/fmolb.2026.1852012"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1852012","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"article-number":"1852012"}}