Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome

Chi Bun Chan, Michiyo Abe, Noriyoshi Hashimoto, Chunhai Hao, Ifor R. Williams, Xia Liu, Shinji Nakao, Akitsugu Yamamoto, Shi Yong Li, Ikuko Hara-Nishimura, Masahide Asano, Keqiang Ye

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)468-473
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number2
DOIs
StatePublished - Jan 13 2009

Keywords

  • Hematopoiesis
  • Legumain
  • Lysosomal disorder
  • Macrophage

ASJC Scopus subject areas

  • General

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    Chan, C. B., Abe, M., Hashimoto, N., Hao, C., Williams, I. R., Liu, X., Nakao, S., Yamamoto, A., Li, S. Y., Hara-Nishimura, I., Asano, M., & Ye, K. (2009). Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. Proceedings of the National Academy of Sciences of the United States of America, 106(2), 468-473. https://doi.org/10.1073/pnas.0809824105