Napsins: new human aspartic proteinases

Tatnell, Peter J.; Powell, David J.; Hill, John; Smith, Trudi S.; Tew, David G.; Kay, John

doi:10.1016/s0014-5793(98)01522-1

Cited by 75 publications

(31 citation statements)

References 22 publications

(26 reference statements)

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“…Other genes novel in this context and putatively important for Th1 cell differentiation and/or function include METRNL , (meteorin, glial cell differentiation regulator-like), associated with rare cases of Mild ring 17 syndrome [32], GLUL encoding a glutamine synthetase, and associated with neuronal disorders and atherosclerotic carotid plaques [33,34], MCTP2 (multiple C2 domains, trans membrane 2), BBS12 (Bardet-Biedl syndrome 12), STAG3 (stromal antigen 3), a meiotic gene, as well as PGAP1 (post-GPI attachment to proteins 1). NAPSB coding for aspartic protease Napsin B is known to be expressed in human spleen and peripheral blood leucocytes, however, it is estimated to be only a transcribed pseudogene [35,36]. Similarly, MIAT (myocardial infarction associated transcript) is a non-protein coding gene [37], and the relevance of these transcripts in T cell differentiation is not understood, yet.…”

Section: Resultsmentioning

confidence: 99%

An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation

et al. 2012

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BackgroundA proper balance between different T helper (Th) cell subsets is necessary for normal functioning of the adaptive immune system. Revealing key genes and pathways driving the differentiation to distinct Th cell lineages provides important insight into underlying molecular mechanisms and new opportunities for modulating the immune response. Previous computational methods to quantify and visualize kinetic differential expression data of three or more lineages to identify reciprocally regulated genes have relied on clustering approaches and regression methods which have time as a factor, but have lacked methods which explicitly model temporal behavior.ResultsWe studied transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation. To identify genes that exhibit distinct lineage commitment dynamics and are specific for initiating differentiation to different Th cell subsets, we developed a novel computational methodology (LIGAP) allowing integrative analysis and visualization of multiple lineages over whole time-course profiles. Applying LIGAP to time-course data from multiple Th cell lineages, we identified and experimentally validated several differentially regulated Th cell subset specific genes as well as reciprocally regulated genes. Combining differentially regulated transcriptional profiles with transcription factor binding site and pathway information, we identified previously known and new putative transcriptional mechanisms involved in Th cell subset differentiation. All differentially regulated genes among the lineages together with an implementation of LIGAP are provided as an open-source resource.ConclusionsThe LIGAP method is widely applicable to quantify differential time-course dynamics of many types of datasets and generalizes to any number of conditions. It summarizes all the time-course measurements together with the associated uncertainty for visualization and manual assessment purposes. Here we identified novel human Th subset specific transcripts as well as regulatory mechanisms important for the initiation of the Th cell subset differentiation.

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Section: Resultsmentioning

confidence: 99%

An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation

et al. 2012

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“…Recently a new aspartic proteinase has been described in humans and mouse, respectively [5,6]. This new human enzyme, called napsin, is found in two isoforms, napsin A and B, which share high sequence homology (85%).…”

Section: Introductionmentioning

confidence: 99%

“…While napsin A seems to be a functional aspartic proteinase predominantly expressed in lung and kidney, napsin B is transcribed exclusively in cells associated with the immune system. Tatnell et al suggest that napsin B might be a transcribed pseudogene lacking a stop codon and as a result it is possible that the protein product is rapidly degraded and, therefore, difficult to detect [5]. Human aspartic proteinases pepsin and gastricsin are secreted by the stomach, cathepsin E is found in the endoplasmatic reticulum of erythrocytes and stomach mucosa cells [7], whereas cathepsin D is located in lysosomes of various cell types.…”

Section: Introductionmentioning

confidence: 99%

Human napsin A: expression, immunochemical detection, and tissue localization

et al. 1999

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A novel aspartic proteinase, called napsin, has recently been found in human and mouse. Due to high similarity with cathepsin D a structural model of human napsin A could be built. Based on this model a potential epitope SFYLNRD-PEEPDGGE has been identified, which was used to immunize rabbits. The resulting antibody was employed in monitoring the expression of recombinant human napsin A in HEK293 cell line. Western blot analysis confirmed the specificity of the antibody and showed that human napsin A is expressed as a single chain protein with the molecular weight of approximately 38 kDa. Immunohistochemical studies revealed high expression levels of napsin A in human kidney and lung but low expression in spleen.z 1999 Federation of European Biochemical Societies.

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“…Recently, a novel aspartic protease, napsin A, was localized in type-II pneumocytes of the human lung by immunohistochemistry as well as in situ hybridization (13)(14)(15). The restricted tissue localization of napsin A in the lung suggests distinct physiological functions.…”

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Involvement of Napsin A in the C- and N-terminal Processing of Surfactant Protein B in Type-II Pneumocytes of the Human Lung

Brasch

Ochs

Kähne

et al. 2003

Journal of Biological Chemistry

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Surfactant protein B (SP-B) is a critical component of pulmonary surfactant, and a deficiency of active SP-B results in fatal respiratory failure. SP-B is synthesized by type-II pneumocytes as a 42-kDa propeptide (proSP-B), which is posttranslationally processed to an 8-kDa surface-active protein. Napsin A is an aspartic protease expressed in type-II pneumocytes. To characterize the role of napsin A in the processing of proSP-B, we colocalized napsin A and precursors of SP-B as well as SP-B in the Golgi complex, multivesicular, composite, and lamellar bodies of type-II pneumocytes in human lungs using immunogold labeling. Furthermore, we measured aspartic protease activity in isolated lamellar bodies as well as isolated human type-II pneumocytes and studied the cleavage of proSP-B by napsin A and isolated lamellar bodies in vitro. Both, napsin A and isolated lamellar bodies cleaved proSP-B and generated three identical processing products. Processing of proSP-B by isolated lamellar bodies was completely inhibited by an aspartic protease inhibitor. Sequence analysis of proSP-B processing products revealed several cleavage sites in the Nand C-terminal propeptides as well as one in the mature peptide. Two of the four processing products generated in vitro were also detected in type-II pneumocytes. In conclusion, our results show that napsin A is involved in the N-and C-terminal processing of proSP-B in type-II pneumocytes.The integrity and function of pulmonary surfactant are of paramount importance for lung function. Disturbance of surfactant activity leads to respiratory distress (1). The main function of pulmonary surfactant is the reduction of the surface tension at the air/liquid interface in the lung, thus preventing alveolar collapse at end-expiration. Pulmonary surfactant is a complex mixture of ϳ90% lipids and ϳ10% proteins that is synthesized, stored, secreted, and to a large extent recycled by type-II pneumocytes of the alveolar epithelium.The hydrophobic surfactant protein B (SP-B) 1 interacts with phospholipids and contributes to the formation of intracellular lamellar bodies, the structural rearrangement of secreted surfactant lipids into tubular myelin, as well as the subsequent rapid insertion of secreted surfactant phospholipids into the surface film (reviewed in Ref. 2). Hereditary SP-B deficiency in infants or mice leads to respiratory failure at birth (3-6). However, hereditary alveolar proteinosis in babies without any detectable mutations in the SP-B gene as well as acquired pulmonary alveolar proteinosis in children and adults are characterized by an intraalveolar accumulation of mature surfactant proteins and abnormal SP-B precursors. Furthermore, only SP-B precursors are detected in babies with congenital surfactant defects characterized by the absence of lamellar bodies in type-II pneumocytes.2 Therefore, insufficient processing of proSP-B due to a lack or dysfunction of one or more proteases involved in SP-B processing might be yet another undiscovered cause of surfactant dysfunction in p...

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Napsins: new human aspartic proteinases

Cited by 75 publications

References 22 publications

An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation

An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation

Human napsin A: expression, immunochemical detection, and tissue localization

Involvement of Napsin A in the C- and N-terminal Processing of Surfactant Protein B in Type-II Pneumocytes of the Human Lung

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