title: Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Chi-Bun
authors.initials: CB
authors.lastname: Chan
authors.forename: Michiyo
authors.initials: M
authors.lastname: Abe
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Chunhai
authors.initials: C
authors.lastname: Hao
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Chengyun
authors.initials: C
authors.lastname: Zheng
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Marie
authors.initials: M
authors.lastname: Meeths
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjold
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Li
authors.forename: Ikuko
authors.initials: I
authors.lastname: Hara-Nishimura
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000172:deficiency*; D006411:Hematopoiesis, Extramedullary; D007694:Killer Cells, Natural; D051359:Lymphohistiocytosis, Hemophagocytic / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010198:Pancytopenia; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly; D000099240:Asparaginyl Endopeptidase
chemical_list: D003546:Cysteine Endopeptidases; D000099240:Asparaginyl Endopeptidase