Potential involvement of ubiquitin-proteasome system dysfunction associated with oxidative stress in the pathogenesis of sickle cell disease
Potential involvement of ubiquitin-proteasome system dysfunction associated with oxidative stress in the pathogenesis of sickle cell disease
复制标题
与氧化应激相关的泛素蛋白酶体系统功能障碍可能参与镰状细胞病的发病机制
DOI：
10.1111/bjh.15437
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发表时间：
2018
影响因子：
6.5
通讯作者：
Mukherjee Malay B.
中科院分区：
文献类型：
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作者：
Warang Prashant;Homma Takujiro;Pandya Riddhi;Sawant Anuja;Shinde Nikhil;Pandey Debjeet;Fujii Junichi;Madkaikar Manisha;Mukherjee Malay B.
泛素-蛋白酶体系统（UPS）是一种重要的细胞内蛋白水解途径，负责蛋白质的降解和氧化损伤;因此，它在维持红细胞（RBC）的稳态中起着核心作用。本研究探讨了镰状细胞病（SCD）患者红细胞中多聚泛素化水平、蛋白酶体功能以及羟基脲（HC）治疗的影响。与HC治疗的SCD患者（HC-SCD）和对照组相比，发现未治疗的SCD（UT-SCD）患者中的聚泛素化蛋白升高。UT-SCD患者中β1和β2亚基的活性略高，与UT-SCD患者和对照组相比，在HC-SCD患者的RBC的所有三个亚基（β1、β2和β5）中观察到更高的蛋白水解活性，尽管这些亚基的蛋白水平保持大致相同。值得注意的是，尽管HC治疗，一些患者表现出持续的并发症和聚泛素化蛋白的积累。HC治疗患者中蛋白酶体活性的增强可能会清除多聚泛素化蛋白，可能是治疗作用的重要机制之一。这些发现可能有助于了解SCD的病理生理学及其临床异质性，并确定一个合适的治疗目标，以更好地管理这些患者。
The ubiquitin‐proteasome system (UPS) is an important intracellular proteolytic pathway responsible for the degradation of proteins and oxidative damage; hence it plays a central role in maintaining homeostasis of red blood cells (RBCs). The present study investigated the levels of polyubiquitination, the function of proteasomes and effect of hydroxycarbamide (HC) therapy in RBCs from sickle cell disease (SCD) patients. Polyubiquitinated proteins were found to be elevated in untreated SCD (UT‐SCD) patients compared to those in HC‐treated SCD patients (HC‐SCD) and controls. Activities of β1 and β2 subunits were a little higher in UT‐SCD patients, and much higher proteolytic activities were observed in all three subunits (β1, β2 and β5) of RBCs in HC‐SCD patients compared to those of UT‐SCD patients and controls, although the protein levels of these subunits remained approximately the same. It is notable that, despite HC therapy, some patients showed persistent complications and accumulation of polyubiquitinated proteins. The enhanced proteasomal activity among HC‐treated patients might remove the polyubiquitinated protein and could be one of the important mechanisms of therapeutic action. These findings could be useful to understand the pathophysiology of SCD and its clinical heterogeneity and identify a suitable therapeutic target for the better management of these patients.