{"doi":"10.1016/j.jbc.2021.101281","title":"The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover","abstract":"As a major component of the extracellular matrix, hyaluronan (HA) plays an important role in defining the biochemical and biophysical properties of tissues. In light of the extremely rapid turnover of HA and the impact of this turnover on HA biology, elucidating the molecular mechanisms underlying HA catabolism is key to understanding the in vivo functions of this unique polysaccharide. Here, we show that TMEM2, a recently identified cell surface hyaluronidase, plays an essential role in systemic HA turnover. Employing induced global Tmem2 knockout mice (Tmem2iKO), we determined the effects of Tmem2 ablation not only on the accumulation of HA in bodily fluids and organs, but also on the process of HA degradation in vivo. Within 3 weeks of tamoxifen-induced Tmem2 ablation, Tmem2iKO mice exhibit pronounced accumulation of HA in circulating blood and various organs, reaching levels as high as 40-fold above levels observed in control mice. Experiments using lymphatic and vascular injection of fluorescent HA tracers demonstrate that ongoing HA degradation in the lymphatic system and the liver is significantly impaired in Tmem2iKO mice. We also show that Tmem2 is strongly expressed in endothelial cells in the subcapsular sinus of lymph nodes and in the liver sinusoid, two primary sites implicated in systemic HA turnover. Our results establish TMEM2 as a physiologically relevant hyaluronidase with an essential role in systemic HA catabolism in vivo, acting primarily on the surface of endothelial cells in the lymph nodes and liver. As a major component of the extracellular matrix, hyaluronan (HA) plays an important role in defining the biochemical and biophysical properties of tissues. In light of the extremely rapid turnover of HA and the impact of this turnover on HA biology, elucidating the molecular mechanisms underlying HA catabolism is key to understanding the in vivo functions of this unique polysaccharide. Here, we show that TMEM2, a recently identified cell surface hyaluronidase, plays an essential role in systemic HA turnover. Employing induced global Tmem2 knockout mice (Tmem2iKO), we determined the effects of Tmem2 ablation not only on the accumulation of HA in bodily fluids and organs, but also on the process of HA degradation in vivo. Within 3 weeks of tamoxifen-induced Tmem2 ablation, Tmem2iKO mice exhibit pronounced accumulation of HA in circulating blood and various organs, reaching levels as high as 40-fold above levels observed in control mice. Experiments using lymphatic and vascular injection of fluorescent HA tracers demonstrate that ongoing HA degradation in the lymphatic system and the liver is significantly impaired in Tmem2iKO mice. We also show that Tmem2 is strongly expressed in endothelial cells in the subcapsular sinus of lymph nodes and in the liver sinusoid, two primary sites implicated in systemic HA turnover. Our results establish TMEM2 as a physiologically relevant hyaluronidase with an essential role in systemic HA catabolism in vivo, acting primarily on the surface of endothelial cells in the lymph nodes and liver. Hyaluronan (HA), a member of the family of glycosaminoglycans (GAGs), is a long unbranched polysaccharide (as along as 25,000 disaccharide units in length) with a molecular weight reaching as high as 107 Da. HA is a major component of the extracellular matrix (ECM) and is also present in biological fluids, such as blood and lymph (1Laurent T.C. Fraser J.R. Hyaluronan.FASEB J. 1992; 6: 2397-2404Crossref PubMed Scopus (2041) Google Scholar, 2Hascall V. Esko J.D. Hyaluronan.in: rd Varki A. Cummings R.D. Esko J.D. Stanley P. Hart G.W. Aebi M. Darvill A.G. Kinoshita T. Packer N.H. Prestegard J.H. Schnaar R.L. Seeberger P.H. Essentials of Glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2015: 197-206Google Scholar, 3Toole B.P. Hyaluronan: From extracellular glue to pericellular cue.Nat. Rev. Cancer. 2004; 4: 528-539Crossref PubMed Scopus (1603) Google Scholar). HA is ex","journal":"Journal of Biological Chemistry","year":2021,"id":162963,"datarank":0.5709993734655481,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"self_citation_contribution":0.5709993734655481,"citation_network_contribution":0.0,"self_endowment_contribution":0.5709993734655481,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":681549,"name":"Naoki Fujita","orcid":"0000-0001-8284-9582","position":1,"is_corresponding":false},{"id":678351,"name":"Hayato Yamamoto","orcid":"0000-0002-4557-0619","position":2,"is_corresponding":false},{"id":581057,"name":"Chikara Οhyama","orcid":"0000-0003-1550-8379","position":3,"is_corresponding":false},{"id":678349,"name":"Fumitoshi Irie","orcid":"0000-0001-6363-7808","position":4,"is_corresponding":false},{"id":382727,"name":"Yu Yamaguchi","orcid":"0000-0003-0098-281X","position":5,"is_corresponding":false},{"id":678350,"name":"Yuki Tobisawa","orcid":"0000-0001-8026-9541","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:45:17.971865Z","pmid":"34624311","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}