Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome.
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.
Chan
Chi-Bun
CB
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Abe
Michiyo
M
Hashimoto
Noriyoshi
N
Hao
Chunhai
C
Williams
Ifor R
IR
Liu
Xia
X
Nakao
Shinji
S
Yamamoto
Akitsugu
A
Zheng
Chengyun
C
Henter
Jan-Inge
JI
Meeths
Marie
M
Nordenskjold
Magnus
M
Li
Shi-Yong
SY
Hara-Nishimura
Ikuko
I
Asano
Masahide
M
Ye
Keqiang
K
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
D003546:Cysteine Endopeptidases; D000099240:Asparaginyl Endopeptidase