Proteasomal chymotrypsin‐like peptidase activity is required for essential functions of human monocyte‐derived dendritic cells
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Summary: The ubiquitin–proteasome pathway is the principal system for extralysosomal protein degradation in eukaryotic cells, and is essential for the regulation and maintenance of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. The 26S proteasome, a large multicatalytic protease complex, constitutes the system's proteolytic core machinery that exhibits different proteolytic activities residing in defined proteasomal subunits. We have identified proteasome inhibitors – bortezomib, epoxomicin and lactacystin – which selectively inhibit the proteasomal β5 subunit‐located chymotrypsin‐like peptidase activity in human monocyte‐derived dendritic cells (DCs). Inhibition of proteasomal chymotrypsin‐like peptidase activity in immature and mature DCs impairs the cell‐surface expression of CD40, CD86, CD80, human leucocyte antigen (HLA)‐DR, CD206 and CD209, induces apoptosis, and impairs maturation of DCs, as demonstrated by decreased cell‐surface expression of CD83 and lack of nuclear translocation of RelA and RelB. Inhibition of chymotrypsin‐like peptidase activity abrogates macropinocytosis and receptor‐mediated endocytosis of macromolecular antigens in immature DCs, and inhibits the synthesis of interleukin (IL)‐12p70 and IL‐12p40 in mature DCs. As a functional consequence, DCs fail to stimulate allogeneic CD4+ and CD8+ T cells and autologous CD4+ T cells sufficiently in response to inhibition of chymotrypsin‐like peptidase activity. Thus, proteasomal chymotrypsin‐like peptidase activity is required for essential functions of human DCs, and inhibition of proteasomal chymotrypsin‐like peptidase activity by selective inhibitors, or by targeting β5 subunit expression, may provide a novel therapeutic strategy for suppression of deregulated and unwanted immune responses.
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PIs may have immunomodulatory role in suppressing dendritic cells function and downstream T-cell stimulation.
“In addition, these inhibitors may have immunomodulatory role in suppressing dendritic cells function and downstream T-cell stimulation (86).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [86]
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Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies
Chu, W. S., & Ng, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.658038 · Cited by 59 · see citing works
- Authors
- Naujokat, C., Berges, C., Höh, A., Wieczorek, H., Fuchs, D., Ovens, J., Miltz, M., Sadeghi, M., Opelz, G., & Daniel, V.
- Affiliations
- Heidelberg University (DE)
- Corresponding author
- Naujokat, Cord
- Daniel, Volker
- Venue
- Immunology
- Publisher
- Wiley
- Published
- 2007-01
- Volume
- 120
- Issue
- 1
- Pages
- 120-132
- ISSN
- 0019-2805 (ISSN-L)
- 1365-2567
- PMC
- PMC2265869
- OpenAlex
- W2076344904
- Cited by
- 41
- References
- 53
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 4 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 2 · 2013: 5 · 2012: 2
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- proteasome, beta5 subunit, monocyte-derived dendritic cells, dendritic cell maturation, proteasome inhibitors, bortezomib, epoxomicin, lactacystin, antigen uptake, IL-12, T cell stimulation, dendritic cell surface markers, p65 nuclear translocation, immunosuppression
- MeSH terms
- Bortezomib, Acetylcysteine, Boronic Acids, Cell Differentiation, Dendritic Cells, Endocytosis, Humans, Lymphocyte Activation, Monocytes, Oligopeptides, Pinocytosis, Protease Inhibitors, Pyrazines, Receptors, Cell Surface, Cysteine Proteinase Inhibitors, Apoptosis, Interleukin-12, Proteasome Endopeptidase Complex, Chymases
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