{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:49:21Z","timestamp":1777438161296,"version":"3.51.4"},"reference-count":82,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,26]],"date-time":"2020-04-26T00:00:00Z","timestamp":1587859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00HL131866"],"award-info":[{"award-number":["R00HL131866"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P40OD012095"],"award-info":[{"award-number":["P40OD012095"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM086524"],"award-info":[{"award-number":["R01GM086524"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth factor signaling has been identified as a contributor to the phenotypes associated with ML-II and other lysosomal disorders but an understanding of how these signaling pathways are affected is still emerging. Here, we investigated transforming growth factor beta 1 (TGF\u03b21) signaling in the context of ML-II patient fibroblasts, observing decreased TGF\u03b21 signaling that was accompanied by impaired TGF\u03b21-dependent wound closure. We found increased intracellular latent TGF\u03b21 complexes, caused by reduced secretion and stable localization in detergent-resistant lysosomes. Sortilin, a sorting receptor for hydrolases and TGF\u03b2-related cytokines, was upregulated in ML-II fibroblasts as well as GNPTAB-null HeLa cells, suggesting a mechanism for inappropriate lysosomal targeting of TGF\u03b2. Co-expression of sortilin and TGF\u03b2 in HeLa cells resulted in reduced TGF\u03b21 secretion. Elevated sortilin levels correlated with normal levels of cathepsin D in ML-II cells, consistent with a compensatory role for this receptor in lysosomal hydrolase targeting. Collectively, these data support a model whereby sortilin upregulation in cells with lysosomal storage maintains hydrolase sorting but suppresses TGF\u03b21 secretion through increased lysosomal delivery. These findings highlight an unexpected link between impaired lysosomal sorting and altered growth factor bioavailability.<\/jats:p>","DOI":"10.3390\/biom10050670","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T10:30:58Z","timestamp":1588069858000},"page":"670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGF\u03b2 in Mucolipidosis II Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Jarrod W.","family":"Barnes","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Aarnio-Peterson","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joy","family":"Norris","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Haskins","sequence":"additional","affiliation":[{"name":"Emeritus Professor, Pathology and Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Flanagan-Steet","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4963","authenticated-orcid":false,"given":"Richard","family":"Steet","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1172\/JCI110189","article-title":"Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in uridine 5\u2019-diphosphate-N-acetylglucosamine: Glycoprotein N-acetylglucosaminylphosphotransferase activity","volume":"67","author":"Reitman","year":"1981","journal-title":"J. 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