Cathepsin E Deficiency Induces a Novel Form of Lysosomal Storage Disorder Showing the Accumulation of Lysosomal Membrane Sialoglycoproteins and the Elevation of Lysosomal pH in Macrophages

Yanagawa, Masumi; Tsukuba, Takayuki; Nishioku, Tsuyoshi; Okamoto, Yoshiharu; Okamoto, Kuniaki; Takii, Ryosuke; Terada, Yoshihiro; Nakayama, Keiichi I.; Kadowaki, Tomoko; Yamamoto, Kazuo

doi:10.1074/jbc.m604143200

Cited by 55 publications

(60 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since an elevated pH is known to induce abnormal properties of endolysosomal compartments including abnormal processing and targeting of lysosomal proteins (10,11) and abnormal maturation and/or fusion events of the acidic organelles (12), CatE -/-macrophages are assumed to show trafficking defects in both membrane and soluble proteins. Indeed, we found the enhanced secretion of soluble lysosomal enzymes by CatE -/-macrophages (9). In addition to soluble proteins, we reported decreased surface levels of Toll-like receptors (TLRs), which are capable of recognizing specific components of microorganisms, in CatE -/-macrophages, further we reported diminished cytokine production by CatE -/-macrophages that are stimulated by specific TLR ligands (8).…”

Section: Introductionmentioning

confidence: 76%

“…Recently, we demonstrated that peritoneal macrophages derived from CatE -/-mice display a novel type of lysosomal storage disorder characterized by the accumulation of major lysosomal membrane sialoglycoproteins such as lysosome-associated membrane protein (LAMP)-1 and LAMP-2, in the cells with a concomitant elevated lysosomal pH (9). Since an elevated pH is known to induce abnormal properties of endolysosomal compartments including abnormal processing and targeting of lysosomal proteins (10,11) and abnormal maturation and/or fusion events of the acidic organelles (12), CatE -/-macrophages are assumed to show trafficking defects in both membrane and soluble proteins.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

Tsukuba

Yanagawa

Okamoto

et al. 2009

Journal of Biochemistry

View full text Add to dashboard Cite

SUMMARYCathepsin E is an endo-lysosomal aspartic proteinase exclusively present in immune system cells. Previous studies have shown that cathepsin E-deficient (CatE -/-) mice display aberrant immune responses such as atopic dermatitis and higher susceptibility to bacterial infection.However, the mechanisms underlying abnormal immune responses induced by cathepsin E deficiency are still unclear. In this study, we found that the cell-surface levels of chemotactic 3

show abstract

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

Tsukuba

Yanagawa

Okamoto

et al. 2009

Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…Wild-type and CatE -/-mice with the C57BL/6 genetic background were used as described previously [7,8]. Animals were maintained under specific pathogen-free conditions according to the guidelines of the Japanese Pharmacological Society.…”

Section: Micementioning

confidence: 99%

“…Recently, we reported that macrophages derived from CatE -/-mice display a novel type of lysosomal storage disorder, characterized by accumulation of lysosomal membrane glycoproteins such as LAMP-1 and LAMP-2, in cells with a concomitant elevated lysosomal pH [8]. In particular, CatE -/-macrophages exhibit various abnormalities, such as reduced bactericidal activity [9], trafficking defects for both membrane and soluble proteins [10], and impaired TNF-α or IL-6 production [9].…”

Section: Introductionmentioning

confidence: 99%

Defective adipose tissue development associated with hepatomegaly in cathepsin E-deficient mice fed a high-fat diet

Kadowaki

Kido

Hatakeyama

et al. 2014

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Running title: Fat-induced cathepsin E-deficient mice Key words: cathepsin E, high-fat diet, adipose tissue AbstractCathepsin E is an intracellular aspartic proteinase, which is predominantly distributed in immune-related and epithelial cells. However, the role of the enzyme in adipose tissues remains unknown. In this study, we investigated the characteristics of cathepsin E-deficient (CatE -/-) mice fed a high-fat diet (HFD), as a mouse model of obesity. HFD-fed CatE -/-mice displayed reduced body weight gain and defective development of white adipose tissue (WAT) and brown adipose tissue (BAT), compared with HFD-fed wild-type mice. Moreover, fat-induced CatE -/-mice showed abnormal lipid accumulation in non-adipose tissues characterized by hepatomegaly, which is probably due to defective adipose tissue development. Detailed pathological and biochemical analyses showed that hepatomegaly was accompanied by hepatic steatosis and hypercholesterolemia in HFD-induced CatE -/-mice. In fat-induced CatE -/-mice, the number of macrophages infiltrating into WAT was significantly lower than in fat-induced wild-type mice. Thus, the impaired adipose tissue development in HFD-induced CatE -/-mice was probably due to reduced infiltration of macrophages and may lead to hepatomegaly accompanied by hepatic steatosis and hypercholesterolemia.

show abstract

“…CTSE deficiency also is associated with a novel form of lysosomal storage disorder in macrophages [6]. A related protease, cathepsin D, has been implicated in the degradation of extracellular matrix proteins [7].…”

mentioning

confidence: 99%

Regulation of the human cathepsin E gene by the constitutive androstane receptor

Page

Strom

Omiecinski

2007

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Cathepsin E (CTSE) is an aspartic protease that has been linked to antigen processing and innate immunity. Elevated levels of CTSE expression have also been associated with several forms of cancer, including carcinomas exhibiting highly invasive character. In this study, we performed DNA microarray experiments, together with quantitative reverse transcriptase PCR analyses and enzymatic activity determinations to identify human CTSE as a novel target gene for regulation by the constitutive androstane receptor (CAR), a nuclear receptor activated by the liver tumor promoting agent, phenobarbital. In particular, two motifs within the 5′-flanking region of the human CTSE gene were identified as direct sites of interaction with CAR/RXRα heterodimers, a direct repeat-3 site at position −766 and a direct repeat-4 site at position −1407. Thus, these studies demonstrate CAR-mediated regulation of CTSE within primary hepatocyte cultures from several individual donors and suggest that elevated CTSE activity may play a functional role in the etiology of hepatocarcinogenesis. KeywordsCathepsin E; Constitutive androstane receptor; Hepatocytes; Primary hepatocytes; Liver; Human; Hepatocytes Cathepsin E (CTSE) 1 is an intracellular aspartic protease that hydrolyzes various biologically active peptides [1]. Unlike related proteases, CTSE is localized outside of the lysosomal system and likely functions in extralysosomal proteolysis [2]. Although its exact biological functions remain elusive, several physiological roles of CTSE have been reported, including roles in immune defense and antigen processing [3][4][5]. In this respect, CTSEdeficient mice exhibit markedly increased susceptibility to both gram positive and gram negative bacterial infection, likely due to impaired regulation of bacterial elimination [5]. Given the apparent association of enhanced CTSE expression with hepatocellular carcinoma, we hypothesize that liver tumor promoting agents may function to enhance CTSE expression levels in liver and that increased proteolytic activity may underlie certain mechanistic aspects of the tumor promotion process. In the studies reported here, we identify CTSE expression in human hepatoctyes. In particular, microarray expression profiling analyses indicated that exposures to the classical liver tumor promoter, phenobarbital (PB), resulted in increased CTSE transcript levels within primary hepatocyte cultures from several individual donors, a result that was confirmed by quantitative RT-PCR experiments. Further, we demonstrate that the constitutive androstane receptor (CAR) acts as a transcriptional regulator of the human CTSE gene and that these events lead to PB-inducible increases in functional hepatic CTSE enzymatic activity. Materials and methods ChemicalsPhenobarbital sodium salt was obtained from UWMC Drug Services (Seattle, WA). Clotrimazole, meclizine and dimethyl sulfoxide (DMSO) were purchased from Sigma (St. Louis, MO). CITCO was purchased from BIOMOL Research Laboratories (Plymouth Meeting, PA). Cell cultureCO...

show abstract

Cathepsin E Deficiency Induces a Novel Form of Lysosomal Storage Disorder Showing the Accumulation of Lysosomal Membrane Sialoglycoproteins and the Elevation of Lysosomal pH in Macrophages

Cited by 55 publications

References 45 publications

Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

Defective adipose tissue development associated with hepatomegaly in cathepsin E-deficient mice fed a high-fat diet

Regulation of the human cathepsin E gene by the constitutive androstane receptor

Contact Info

Product

Resources

About