Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome
Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome
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DOI：
10.1073/pnas.0809824105
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发表时间：
2009-01-13
影响因子：
11.1
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Chan, Chi-Bun;Abe, Michiyo;Ye, Keqiang
天冬酰胺酰内肽酶（AEP 或 legumain）是一种溶酶体半胱氨酸蛋白酶，可裂解天冬酰胺 C 末端的蛋白质底物。 AEP 在内体/溶酶体降解系统中发挥关键作用，并参与抗原加工。在 AEP 缺陷小鼠中，肾脏中溶酶体蛋白酶组织蛋白酶的加工完全有缺陷，溶酶体中大分子积聚，这通常见于溶酶体疾病。在这里，我们发现缺乏AEP的突变小鼠会出现发热、血细胞减少、肝脾肿大和噬血细胞增多症，这是噬血细胞综合征/噬血细胞性淋巴组织细胞增多症（HLH）的主要病理表现。此外，AEP 缺乏会引起脾脏中的髓外造血和骨髓中摄入红细胞 (RBC) 的组织细胞异常增大。有趣的是，AEP 缺失小鼠的红细胞质膜成分有缺陷。此外，AEP 缺失小鼠表现出较低的自然杀伤细胞活性，但主要细胞因子均无明显异常。这些结果表明，AEP 可能是 HLH 病理生理学中以前未被认识的组成部分。
Asparaginyl endopeptidase (AEP or legumain) is a lysosomal cysteine protease that cleaves protein substrates on the C-terminal side of asparagine. AEP plays a pivotal role in the endosome/ lysosomal degradation system and is implicated in antigen processing. The processing of the lysosomal proteases cathepsins in kidney is completely defective in AEP-deficient mice with accumulation of macromolecules in the lysosomes, which is typically seen in lysosomal disorders. Here we show that mutant mice lacking AEP develop fever, cytopenia, hepatosplenomegaly, and hemophagocytosis, which are primary pathological manifestations of hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (HLH). Moreover, AEP deficiency provokes extramedullary hematopoiesis in the spleen and abnormally enlarged histiocytes with ingested red blood cells (RBCs) in bone marrow. Interestingly, RBCs from AEP-null mice are defective in plasma membrane components. Further, AEP-null mice display lower natural killer cell activity, but none of the major cytokines is substantially abnormal. These results indicate that AEP might be a previously unrecognized component in HLH pathophysiology.