Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases characterized by glycosaminoglycan (GAG) accumulation causing progressive multi-organs dysfunction and ultimately severe cardio-respiratory damages. Human cystatin C (hCC), a potent inhibitor of cysteine cathepsins, plays an important role in respiratory diseases. However, its regulation remained unknown in MPS. Herein, elevated hCC levels were measured in respiratory specimens from MPS-I, -II, and -III patients and were significantly correlated with severe respiratory symptoms (rs = 0.7173). Heparan sulfate (HS), a prominent GAG, dampened its inhibitory activity toward cathepsin L in a dose-dependent manner. HS and HS-oligosaccharides bound tightly hCC, in combination with a secondary structure rearrangement. Molecular modeling studies identified three HS binding regions in hCC, including the N-terminus, which is crucial in the inhibition of cathepsins. Impairment of inhibitory potential of hCC may reflect abnormal regulation of proteolytic activity of cathepsin L in lung, ultimately contributing to the severity of MPS.

粘多糖贮积症 (MPS) 是一组罕见的溶酶体贮积病，其特征是糖胺聚糖 (GAG) 积累导致进行性多器官功能障碍并最终导致严重的心肺功能损害。人胱抑素 C (hCC) 是半胱氨酸组织蛋白酶的强效抑制剂，在呼吸系统疾病中起重要作用。然而，它的监管在 MPS 中仍然未知。在此，在 MPS-I、-II 和 -III 患者的呼吸道标本中测量了升高的 hCC 水平，并且与严重的呼吸道症状显着相关（rs = 0.7173）。硫酸乙酰肝素 (HS) 是一种突出的 GAG，以剂量依赖性方式抑制其对组织蛋白酶 L 的抑制活性。HS 和 HS-寡糖与二级结构重排结合紧密地结合 hCC。分子模型研究确定了 hCC 中的三个 HS 结合区域，包括 N 末端，这对于抑制组织蛋白酶至关重要。hCC抑制潜力的损害可能反映了肺组织蛋白酶L蛋白水解活性的异常调节，最终导致MPS的严重程度。