Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion

Schulz, Ingo; Zeitschel, Ulrike; Rudolph, Thomas; Ruiz‐Carrillo, David; Rahfeld, Jens‐Ulrich; Gerhartz, Bernd; Bigl, Volker; Demuth, Hans‐Ulrich; Rößner, Steffen

doi:10.1111/j.1471-4159.2005.03237.x

Cited by 97 publications

(111 citation statements)

References 34 publications

(31 reference statements)

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“…These findings support a general association of PREP with secretory processes, at least in spatial terms, as has been proposed by Schulz et al (2005) and us (Myöhänen et al 2008a), possibly via microtubules or the Golgi-endoplasmic reticulum network. However, additional detailed studies of the role of PREP in protein secretion are required to draw more specific conclusions.…”

Section: Discussionsupporting

confidence: 72%

Distribution of Prolyl Oligopeptidase in Human Peripheral Tissues and in Ovarian and Colorectal Tumors

Myöhänen

Pyykkö

Männistö

et al. 2012

J Histochem Cytochem.

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SummaryProlyl oligopeptidase (PREP) is a serine protease that hydrolyzes peptides shorter than 30-mer, and it has been connected with multiple physiological and pathological conditions. PREP has been mostly studied in the brain, but significant PREP activities have been measured in peripheral tissues. Moreover, increased PREP activities have been found in tumors. In this study, the authors studied the immunohistochemical distribution of PREP protein in human peripheral tissues and in ovarian and colorectal tumors. PREP was found to be widely distributed in human peripheral tissues and specifically in certain cells. The most intense PREP expression was seen in the testis, ovaries, liver, and some parts of the skin. At the cellular level, high PREP levels were seen as a rule in secreting epithelial cells and cells involved in reproduction. Increased PREP expression was seen in most of the tumors studied. PREP expression was higher in malignant than benign tumors, and in ovarian epithelial cancers, there was a trend for increased PREP staining with increased malignancy grade. Results suggest that PREP may be associated with secretory processes as well as in reproduction. A more abundant expression of PREP in malignant than benign tumors suggests that PREP may be associated with expansion and metastasis of tumors. (J Histochem Cytochem 60:706-715, 2012)

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Section: Discussionsupporting

confidence: 72%

Distribution of Prolyl Oligopeptidase in Human Peripheral Tissues and in Ovarian and Colorectal Tumors

Myöhänen

Pyykkö

Männistö

et al. 2012

J Histochem Cytochem.

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“…Other putative functions have been hypothesized (18)(19)(20)(21). Due to the lack of any transmembrane region or a lipid anchor domain (1) in PREP's sequence, these functions include participation in the inositol phosphate signaling (18,19), protein secretion, and/or axonal transport (20) and proteinprotein interaction (21).…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

Kim¹,

Toda²,

D’Agostino³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 1. Bone cells express Avprs. Immunofluorescence micrographs (A) and Western immunoblotting (B)show the expression of Avpr1α in osteoblasts and osteoclasts, and as a function of osteoblast (mineralization) and osteoclast (with Rankl) differentiation. The expression of Avp (ligand) and Avpr1α (receptor) in osteoblasts is regulated by 17β-estradiol, as determined by quantitative PCR (C) and Western immunoblotting (D). (Magnification: A, 63×.) Because Avp is a small peptide, its precursor neurophysin II is measured. Statistics: Student t test, P values shown compared with 0 h. Stimulation of Erk phosphorylation (p-Erk) as a function of total Erk (t-Erk) by Avp (10 −8 M) in osteoclast precursors (preosteoclasts), osteoclasts (OC), and osteoblasts establishes functionality of the Avpr1α in the presence or absence of the receptor inhibitor SR49059 (10 −8 M) (E). Western immunoblotting showing the expression of Avpr2 in preosteoclasts, OCs (F), and osteoblasts (G) isolated from Avpr1α −/− mice, as well as in MC3T3.E1 osteoblast precursors (G). Functionality of Avpr2 was confirmed by the demonstration that cells from Avpr1α −/− mice remained responsive to AVP in reducing the expression of osteoblast differentiation genes, namely Runx2, Osx, Bsp, Atf4, Opn, and Osteocalcin (quantitative PCR, P values shown) (H). Only relevant bands from Western blots are shown, with gaps introduced where empty lanes are excised to conserve space.

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“…So far, their physiological function is unclear. Besides their cytosolic localization, AP-B and POP can be localized in intracellular vesicles as well as in nuclei and on the plasma membrane, which depends on the cell type analyzed as well as on cellular activity and developmental status (35)(36)(37). AP-B is implicated to play a role in the processing of glucagon (38) and in the conversion of cholecystokinin 9 (39).…”

Section: Discussionmentioning

confidence: 99%

The Efficiency of Human Cytomegalovirus pp65495–503 CD8+ T Cell Epitope Generation Is Determined by the Balanced Activities of Cytosolic and Endoplasmic Reticulum-Resident Peptidases

Urban

Textoris-Taube

Reimann

et al. 2012

The Journal of Immunology

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Control of human CMV (HCMV) infection depends on the cytotoxic activity of CD8+ CTLs. The HCMV phosphoprotein (pp)65 is a major CTL target Ag and pp65495–503 is an immunodominant CTL epitope in infected HLA-A*0201 individuals. As immunodominance is strongly determined by the surface abundance of the specific epitope, we asked for the components of the cellular Ag processing machinery determining the efficacy of pp65495–503 generation, in particular, for the proteasome, cytosolic peptidases, and endoplasmic reticulum (ER)-resident peptidases. In vitro Ag processing experiments revealed that standard proteasomes and immunoproteasomes generate the minimal 9-mer peptide epitope as well as N-terminal elongated epitope precursors of different lengths. These peptides are largely degraded by the cytosolic peptidases leucine aminopeptidase and tripeptidyl peptidase II, as evidenced by increased pp65495–503 epitope presentation after leucine aminopeptidase and tripeptidyl peptidase II knockdown. Additionally, with prolyl oligopeptidase and aminopeptidase B we identified two new Ag processing machinery components, which by destroying the pp65495–503 epitope limit the availability of the specific peptide pool. In contrast to cytosolic peptidases, silencing of ER aminopeptidases 1 and 2 strongly impaired pp65495–503-specific T cell activation, indicating the importance of ER aminopeptidases in pp65495–503 generation. Thus, cytosolic peptidases primarily interfere with the generation of the pp65495–503 epitope, whereas ER-resident aminopeptidases enhance such generation. As a consequence, our experiments reveal that the combination of cytosolic and ER-resident peptidase activities strongly shape the pool of specific antigenic peptides and thus modulate MHC class I epitope presentation efficiency.

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Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion

Cited by 97 publications

References 34 publications

Distribution of Prolyl Oligopeptidase in Human Peripheral Tissues and in Ovarian and Colorectal Tumors

Distribution of Prolyl Oligopeptidase in Human Peripheral Tissues and in Ovarian and Colorectal Tumors

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

The Efficiency of Human Cytomegalovirus pp65495–503 CD8+ T Cell Epitope Generation Is Determined by the Balanced Activities of Cytosolic and Endoplasmic Reticulum-Resident Peptidases

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