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Unconventional Protein Secretion (EMRC/ECORES/08-EUROMEMBRANE)

English title Unconventional Protein Secretion (EMRC/ECORES/08-EUROMEMBRANE)
Applicant Beer Hans-Dietmar
Number 126141
Funding scheme Project funding (special)
Research institution Dermatologische Klinik Universitätsspital Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Cellular Biology, Cytology
Start/End 01.01.2009 - 31.03.2013
Approved amount 342'615.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Biochemistry

Keywords (9)

unconventional protein secretion; non-classical export; membrane translocation; fibroblast growth fa; inflammation; caspase-1; inflammasome; IL-1; UV irradiation

Lay Summary (English)

Lead
Lay summary
Proteins, which are secreted by non-classical pathways, play important roles in inflammation and repair. The most prominent examples are the pro-inflammatory cytokine IL-1beta and the pro-angiogenic growth factor FGF-2. IL-1beta is initially expressed as an inactive precursor (proIL-1beta), which requires proteolytic processing by the protease caspase-1. In macrophages, caspase-1 itself is activated by recently discovered innate immune complexes, the inflammasomes. These protein complexes act as intracellular stress sensors, which are activated by endogenous danger signals, exogenous toxic compounds, and substances associated with pathogens. We have recently demonstrated that human primary keratinocytes also express inflammasome proteins and that these proteins are required for the UVB-induced activation of proIL-1beta and the secretion of mature IL-1beta. Over macrophages, which are the classic IL-1beta-secreting cells, keratinocytes have several advantages: i) Expression of proIL-1beta is constitutive in keratinocytes, whereas it has to be induced by activators of NF-kappaB in macrophages. ii) Keratinocytes are very robust, which minimizes cell lysis and thereby unspecific release of proteins. iii) In keratinocytes, siRNA transfection allows a very efficient and non-toxic knock-down of the expression of proteins of interest. In summary, UVB-irradiated keratinocytes represent a very powerful and physiological model for the examination of unconventional protein secretion with a high medical relevance. In addition, we identified active caspase-1 as a general regulator of stress-induced unconventional protein secretion. Using iTRAQ proteomics we could show that not only proIL-1beta, FGF-2 and caspase-1 itself but also several other leaderless proteins with known or unknown extracellular functions require caspase-1 activity for efficient unconventional secretion. Many of these proteins are involved in inflammation, apoptosis, detoxification and tissue repair. Therefore, stress-induced activation of caspase-1 links inflammation via unconventional protein secretion directly to cell survival, cytoprotection, and regenerative processes. In this project we perform proteomics experiments, which should allow a better understanding of the mechanism of caspase-1-dependent stress-induced unconventional protein secretion and of its relationship to the constitutive pathway of unconventional secretion.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
132450 The molecular mechanisms underlying UVB-induced caspase-1-dependent apoptosis in keratinocytes 01.10.2010 Project funding
197426 The upstream and downstream regulation of the NLRP1 inflammasome in human keratinocytes 01.10.2020 Project funding

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