The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

Justa-Schuch, Daniela; Möller, Ulrike; Geiss‐Friedlander, Ruth

doi:10.1007/s00018-014-1591-6

Cited by 31 publications

(23 citation statements)

References 48 publications

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“…S1A) with minimal cross‐contamination, verifying the fractionation technique. In line with previous publications , DPP9 was readily detectable in each fraction (Fig. S1A).…”

Section: Resultssupporting

confidence: 92%

“…Recent work demonstrated that alternately translated DPP9 isoforms are localized to different subcellular compartments , necessitating analyses on three separate cell lysate fractions enriched for cytoplasmic, membrane or nuclear proteins. In addition to the cytosolic proteome, about 16% of all DPP9 substrates identified in our study were annotated with nuclear localizations in the UniProt database.…”

Section: Discussionmentioning

confidence: 99%

“…Both DPP8 and DPP9 are diffusely distributed throughout the cell and can be detected in the nucleus. Alternate translation of DPP9 produces two variants, one of which (‘DPP9‐long’) contains a functional nuclear localization sequence . DPP9 activity is regulated by redox state , is allosterically regulated by SUMO1 binding and is implicated in multiple biological processes including immune antigen processing and tumour biology , suggesting general involvements in immunity, transcription and chromatin remodelling .…”

Section: Introductionmentioning

confidence: 99%

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Identification of novel dipeptidyl peptidase 9 substrates by two‐dimensional differential in‐gel electrophoresis

et al. 2015

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Dipeptidyl peptidase 9 (DPP9) is a member of the S9B/DPPIV (DPP4) serine protease family, which cleaves N-terminal dipeptides at an Xaa-Pro consensus motif. Cytoplasmic DPP9 has roles in epidermal growth factor signalling and in antigen processing, whilst the role of the recently discovered nuclear form of DPP9 is unknown. Mice lacking DPP9 proteolytic activity die as neonates. We applied a modified 2D differential in-gel electrophoresis approach to identify novel DPP9 substrates, using mouse embryonic fibroblasts lacking endogenous DPP9 activity. A total of 111 potential new DPP9 substrates were identified, with nine proteins/peptides confirmed as DPP9 substrates by MALDI-TOF or immunoblotting. Moreover, we also identified the dipeptide Val-Ala as a consensus site for DPP9 cleavage that was not recognized by DPP8, suggesting different in vivo roles for these closely related enzymes. The relative kinetics for the cleavage of these nine candidate substrates by DPP9, DPP8 and DPP4 were determined. This is the first identification of DPP9 substrates from cells lacking endogenous DPP9 activity. These data greatly expand the potential roles of DPP9 and suggest different in vivo roles for DPP9 and DPP8.

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“…S1A) with minimal cross‐contamination, verifying the fractionation technique. In line with previous publications , DPP9 was readily detectable in each fraction (Fig. S1A).…”

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of novel dipeptidyl peptidase 9 substrates by two‐dimensional differential in‐gel electrophoresis

et al. 2015

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“…In healthy conditions, the proteases are readily inactivated by the abundant presence of endogenous inhibitors in the cytosol. In cancer cells with reduced expression levels of the inhibitors, however, the proteases remain active and eventually cause severe damage, ultimately leading to cell death cysteine cathepsins and legumain have also been reported in unusual cellular compartments (Justa-Schuch et al 2014;Lee et al 2011;Melo et al 2014).…”

Section: Endo-lysosomal Cysteine Peptidases: Myths and Common Questionsmentioning

confidence: 99%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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“…However, localisation of DPP9 on the surface of immune cells was also reported. In addition, the long form of DPP9 was shown to localise to the nucleus . Redistribution of intracellular DPP9 towards the ruffling membrane upon cell stimulation with phorbol 12‐myristate 13‐acetate or epidermal growth factor has also recently been shown …”

Section: Introductionmentioning

confidence: 87%

Expression, subcellular localisation, and possible roles of dipeptidyl peptidase 9 (DPP9) in murine macrophages

Zapletal

Čupić

Gabrilovac

2017

Cell Biochemistry & Function

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Dipeptidyl peptidase 9 (DPP9) is a peptidase of the DPPIV gene family, and its role in immune responses has been reported. In this study, we compared the messenger RNA expression profile of DPP9 to that of the related DPP8 and DPPIV in murine haematopoietic and lymphatic tissues. A similar order of expression levels was observed for all 3 peptidases: peritoneal macrophages < bone marrow < spleen ≤ lymph nodes. Also, we examined the subcellular localisation of DPP9 and its possible role(s) in J774 cell line of macrophage origin. DPP9 was dominantly expressed intracellularly. DPPIV-like enzymatic activity was mostly present in cytoplasm, but also in cell membranes and organelles/vesicles. Decreased expression of DPP9 was observed upon activation of J774 cells by combined treatment with interferon gamma and lipopolysaccharide. Changes induced by DPP9 gene silencing in J774 cells suggest possible role of DPP9 in regulation of proliferation and activation status. The colocalisation of DPP9 with endocytosed DQ-OVA demonstrated in endosomes of J774 cells might suggest the role of DPP9 in peptide processing within endosomal/vesicular compartment.

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The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

Abstract: was previously considered as a purely cytosolic peptidase, localizes to the nucleus and is active there, raising the intriguing possibility that the longer DPP9 isoform may regulate the activity or stability of nuclear proteins, such as transcription factors.

Cited by 31 publications

References 48 publications

Identification of novel dipeptidyl peptidase 9 substrates by two‐dimensional differential in‐gel electrophoresis

Identification of novel dipeptidyl peptidase 9 substrates by two‐dimensional differential in‐gel electrophoresis

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Expression, subcellular localisation, and possible roles of dipeptidyl peptidase 9 (DPP9) in murine macrophages

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