Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Greenwood Genetic Center, Greenwood, SC 29646, USA.
Biomolecules. 2020 Apr 26;10(5):670. doi: 10.3390/biom10050670.
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 (TGFβ1) signaling in the context of ML-II patient fibroblasts, observing decreased TGFβ1 signaling that was accompanied by impaired TGFβ1-dependent wound closure. We found increased intracellular latent TGFβ1 complexes, caused by reduced secretion and stable localization in detergent-resistant lysosomes. Sortilin, a sorting receptor for hydrolases and TGFβ-related cytokines, was upregulated in ML-II fibroblasts as well as -null HeLa cells, suggesting a mechanism for inappropriate lysosomal targeting of TGFβ. Co-expression of sortilin and TGFβ in HeLa cells resulted in reduced TGFβ1 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 TGFβ1 secretion through increased lysosomal delivery. These findings highlight an unexpected link between impaired lysosomal sorting and altered growth factor bioavailability.
黏脂贮积症 II 型（ML-II）是一种溶酶体疾病，由可溶性水解酶糖基化依赖分选至溶酶体的缺陷引起。已鉴定出生长因子信号转导是与 ML-II 和其他溶酶体疾病相关表型的一个促成因素，但对这些信号通路如何受到影响的理解仍在不断发展。在这里，我们在 ML-II 患者成纤维细胞的背景下研究了转化生长因子β1（TGFβ1）信号转导，观察到 TGFβ1 信号转导减少，同时伴随着 TGFβ1 依赖性伤口闭合受损。我们发现细胞内潜伏 TGFβ1 复合物增加，这是由于分泌减少和在去污剂抗性溶酶体中稳定定位所致。分选素是水解酶和 TGFβ 相关细胞因子的分选受体，在 ML-II 成纤维细胞和 -null HeLa 细胞中上调，这表明存在一种将 TGFβ 不适当靶向溶酶体的机制。在 HeLa 细胞中共表达分选素和 TGFβ 会导致 TGFβ1 分泌减少。分选素水平升高与 ML-II 细胞中组织蛋白酶 D 的正常水平相关，这与该受体在溶酶体水解酶靶向中的代偿作用一致。总的来说，这些数据支持这样一种模型，即溶酶体储存细胞中分选素的上调维持了水解酶的分选，但通过增加溶酶体递送来抑制 TGFβ1 的分泌。这些发现突出了溶酶体分选受损与生长因子生物利用度改变之间的意外联系。
