Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome

Chan, Chi-Bun; Abe, Michiyo; Hashimoto, Noriyoshi; Hao, Chunhai; Williams, Ifor R.; Liu, Xia; Nakao, Shinji; Yamamoto, Akira; Zheng, Chengyun; Henter, Jan‐Inge; Meeths, Marie; Nordenskjöld, Magnus; Li, Shiyong; Hara‐Nishimura, Ikuko; Asano, Masahide; Ye, Keqiang

doi:10.1073/pnas.0809824105

Cited by 69 publications

(70 citation statements)

References 26 publications

(30 reference statements)

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“…Mice deficient in asparaginyl endopeptidase (AEP), an enzyme important for lysosomal degradation, were also reported to develop an HLH-like syndrome including fever, cytopenia, splenomegaly and erythrophagocytosis. 63 Different from human disease, the phagocytozing histiocytes in this model were only consuming red blood cells and not other hematopoetic cells. This was likely due to the fact that these red blood cells had deformed membranes as a result of the AEP deficiency.…”

Section: Proposed Pathophysiology Of Mas In Children With Sjiamentioning

confidence: 82%

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

et al. 2012

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Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30 --40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro-and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

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Section: Proposed Pathophysiology Of Mas In Children With Sjiamentioning

confidence: 82%

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

et al. 2012

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“…We further reported that legumain might have an important role in remodeling of the extracellular matrix through degradation of fibronectin in renal proximal tubular cells [4]. It has been suggested that legumain plays an important role in tumor growth/metastasis, carotid artery-atherosclerosis development [5][6][7][8][9][10][11][12], hemophagocytic syndrome [13] and formation of human unstable carotid plaque [14]. Recently, we reported that degradation of annexin A2 was reduced by knockdown of legumain in the mouse kidney [15].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of the legumain gene by p53 in HCT116 cells

Yamane

Murao

Kato-Ose

et al. 2013

Biochemical and Biophysical Research Communications

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Legumain (EC 3.4.22.34) is an asparaginyl endopeptidase. Strong legumain activity was observed in the mouse kidney, and legumain was found to be highly expressed in tumors. We previously reported that bovine kidney annexin A2 was co-purified with legumain and that legumain cleaved the N-terminal region of annexin A2 at an Asn residue in vitro and in vivo. In this study, we found a p53-binding site in intron 1 of the human legumain gene using computational analysis. To determine whether transcription of the legumain gene is regulated by p53, HCT116 cells were transfected with p53 siRNA and the effect of knockdown of p53 expression on legumain expression was examined. The results showed that expression levels of both legumain mRNA and protein were decreased in the siRNA-treated cells. Furthermore, enzyme activity of legumain was also increased by doxorubicin and its activity was reduced by knockdown of p53 in HCT116 cells. These results suggest that legumain expression and its enzyme activity are regulated by p53.

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“…AEP appears to be autocatalytically cleaved after asparagine or aspartate residue. AEP is also involved in the proteolytic maturation of pro-cathepsins B, H and L found in the endo/lysosomes [4]. In addition to the cathepsins, AEP also processes fibronectin [5], pro-gelatinase A [6] and α-thymosin [7].…”

mentioning

confidence: 99%

Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage

et al. 2014

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Asparaginyl endopeptidase (AEP) is an endo/lysosomal cysteine endopeptidase with a preference for an asparagine residue at the P1 site and plays an important role in the maturation of toll-like receptors 3/7/9. AEP is known to undergo autoproteolytic maturation at acidic pH for catalytic activation. Here, we describe crystal structures of the AEP proenzyme and the mature forms of AEP. Structural comparisons between AEP and caspases revealed similarities in the composition of key residues and in the catalytic mechanism. Mutagenesis studies identified N44, R46, H150, E189, C191, S217/S218 and D233 as residues that are essential for the cleavage of the peptide substrate. During maturation, autoproteolytic cleavage of AEP's cap domain opens up access to the active site on the core domain. Unexpectedly, an intermediate autoproteolytic maturation stage was discovered at approximately pH 4.5 in which the partially activated AEP could be reversed back to its proenzyme form. This unique feature was confirmed by the crystal structure of AEP pH4.5 (AEP was matured at pH 4.5 and crystallized at pH 8.5), in which the broken peptide bonds were religated and the structure was transformed back to its proenzyme form. Additionally, the AEP inhibitor cystatin C could be digested by the fully activated AEP, but could not be digested by activated cathepsins. Thus, we demonstrate for the first time that cystatins may regulate the activity of AEP through substrate competition for the active site.

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Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome

Cited by 69 publications

References 26 publications

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Transcriptional regulation of the legumain gene by p53 in HCT116 cells

Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage

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