The Experts below are selected from a list of 1041 Experts worldwide ranked by ideXlab platform
Walter Nickel - One of the best experts on this subject based on the ideXlab platform.
-
a direct gateway into the extracellular space Unconventional Secretion of fgf2 through self sustained plasma membrane pores
Seminars in Cell & Developmental Biology, 2018Co-Authors: Julia P Steringer, Walter NickelAbstract:Abstract As illustrated by a diverse set of examples in this special issue, multiple mechanisms of Protein Secretion have been identified in eukaryotes that do not involve the endoplasmic reticulum (ER) and the Golgi apparatus. Here we focus on the type I pathway with Fibroblast Growth Factor 2 (FGF2) being the most prominent example. Unconventional Secretion of FGF2 from cells is mediated by direct Protein translocation across the plasma membrane. A unique feature of this process is the ability of FGF2 to form its own membrane translocation intermediate through oligomerization and membrane insertion. This process depends on the phosphoinositide PI(4,5)P2 at the inner leaflet and results in the formation of lipidic membrane pores in the plasma membrane. Various lines of evidence suggest that these pores are characterized by a toroidal architecture with FGF2 oligomers being accommodated in the center of these structures. At the outer leaflet of the plasma membrane, membrane proximal heparan sulfate proteoglycans are required for the final step of FGF2 translocation into the extracellular space. Based upon mutually exclusive interactions of FGF2 with PI(4,5)P2 versus heparan sulfates, an assembly/disassembly pathway has been proposed to be the underlying principle of directional transport of FGF2 across the plasma membrane. Thus, the core mechanism of Unconventional Secretion of FGF2 is based upon three discrete steps with (i) PI(4,5)P2 dependent oligomerization of FGF2 at the inner leaflet, (ii) insertion of membrane spanning FGF2 oligomers into the plasma membrane and (iii) disassembly at the outer leaflet mediated by heparan sulfates that subsequently retain FGF2 on cell surfaces. This process has recently been reconstituted with an inside-out membrane model system using giant unilamellar vesicles providing a compelling explanation of how FGF2 reaches the extracellular space in an ER/Golgi independent manner. This review is part of a Special Issue of SCDB on “Unconventional Protein Secretion” edited by Walter Nickel and Catherine Rabouille.
-
Unconventional Protein Secretion fibroblast growth factor 2 and interleukin 1β as examples
Reference Module in Biomedical Sciences#R##N#Encyclopedia of Cell Biology, 2016Co-Authors: Walter Nickel, Julia P Steringer, Hansmichael Muller, David BroughAbstract:N-terminal signal peptides are a hallmark of the vast majority of soluble secretory Proteins that are transported along the endoplasmic reticulum (ER)/Golgi-dependent pathway. They are recognized by signal recognition particle (SRP), a process that initiates membrane translocation into the lumen of the ER followed by vesicular transport to the cell surface and release into the extracellular space. Beyond this well-established mechanism of Protein Secretion from eukaryotic cells, a number of extracellular Proteins with critical physiological functions in immune surveillance and tissue organization are known to be secreted in an SRP-independent manner. Such processes have collectively been termed ‘Unconventional Protein Secretion’ and, while known for more than two decades, their underlying mechanisms are only beginning to emerge. Different types of Unconventional secretory mechanisms have been described. The aim of this article is to critically assess our current knowledge of this type of Unconventional Secretion focusing on fibroblast growth factor 2 (FGF2) and interleukin-1β as prototypical examples.
-
hiv tat Protein forms phosphoinositide dependent membrane pores implicated in Unconventional Protein Secretion
Journal of Biological Chemistry, 2015Co-Authors: Marcel Zeitler, Hansmichael Muller, Julia P Steringer, Matthias P Mayer, Walter NickelAbstract:HIV-Tat has been demonstrated to be secreted from cells in a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent manner. Here we show that HIV-Tat forms membrane-inserted oligomers, a process that is accompanied by changes in secondary structure with a strong increase in antiparallel β sheet content. Intriguingly, oligomerization of HIV-Tat on membrane surfaces leads to the formation of membrane pores, as demonstrated by physical membrane passage of small fluorescent tracer molecules. Although membrane binding of HIV-Tat did not strictly depend on PI(4,5)P2 but, rather, was mediated by a range of acidic membrane lipids, a functional interaction between PI(4,5)P2 and HIV-Tat was critically required for efficient membrane pore formation by HIV-Tat oligomers. These properties are strikingly similar to what has been reported previously for fibroblast growth factor 2 (FGF2), providing strong evidence of a common core mechanism of Unconventional Secretion shared by HIV-Tat and fibroblast growth factor 2.
-
Unconventional Secretion of fibroblast growth factor 2 a novel type of Protein translocation across membranes
Journal of Molecular Biology, 2015Co-Authors: Julia P Steringer, Hansmichael Muller, Walter NickelAbstract:N-terminal signal peptides are a hallmark of the vast majority of soluble secretory Proteins that are transported along the endoplasmic reticulum/Golgi-dependent pathway. They are recognized by signal recognition particle, a process that initiates membrane translocation into the lumen of the endoplasmic reticulum followed by vesicular transport to the cell surface and release into the extracellular space. Beyond this well-established mechanism of Protein Secretion from eukaryotic cells, a number of extracellular Proteins with critical physiological functions in immune surveillance and tissue organization are known to be secreted in a manner independent of signal recognition particle. Such processes have collectively been termed "Unconventional Protein Secretion" and, while known for more than two decades, their underlying mechanisms are only beginning to emerge. Different types of Unconventional secretory mechanisms have been described with the best-characterized example being based on direct translocation of cytoplasmic Proteins across plasma membranes. The aim of this review is to critically assess our current knowledge of this type of Unconventional Secretion focusing on fibroblast growth factor 2 (FGF2) as the most established example.
-
diversity in Unconventional Protein Secretion
Journal of Cell Science, 2012Co-Authors: Catherine Rabouille, Vivek Malhotra, Walter NickelAbstract:Eukaryotic cells use the endoplasmic reticulum (ER)-to-Golgi membrane pathway for the Secretion of the vast majority of secretory Proteins. This process is initiated by signal-peptide-dependent Protein translocation into the lumen of the ER followed by vesicular transport of secretory cargo to the
Kalle Saksela - One of the best experts on this subject based on the ideXlab platform.
-
hiv 1 nef induced Secretion of the proinflammatory protease tace into extracellular vesicles is mediated by raf 1 and can be suppressed by clinical Protein kinase inhibitors
Journal of Virology, 2021Co-Authors: Zhe Zhao, Riku Fagerlund, Andreas Baur, Kalle SakselaAbstract:Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an Unconventional Protein Secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE Secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger the Secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of Unconventional Protein Secretion and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10% to 40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EVs), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here, we show that Nef promotes uploading of TACE into EVs by triggering Unconventional Secretion via activation of the Hck/Raf/mitogen-activated Protein kinase (MAPK) cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation and could thus provide a novel strategy for treating HIV-associated immune activation.
-
hiv 1 nef induced Secretion of the proinflammatory protease tace into extracellularvesicles is mediated by raf 1 and can be suppressed by clinical Protein kinase inhibitors
Journal of Virology, 2021Co-Authors: Zhe Zhao, Riku Fagerlund, Andreas Baur, Kalle SakselaAbstract:Chronic immune activation is an important driver of HIV-1 pathogenesis, and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EV) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase Hck by HIV-1 Nef can trigger the packaging of TACE into EVs via an Unconventional Protein Secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and SIV Nef alleles we now show that the capacity to promote TACE Secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger Secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of Unconventional Protein Secretion, and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of HIV-1 infection, and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10-40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EV), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here we show that Nef promotes uploading of TACE into EVs by triggering Unconventional Secretion via activation of the Hck/Raf/MAPK kinase cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation, and could thus provide a novel strategy for treating HIV-associated immune activation.
Zhe Zhao - One of the best experts on this subject based on the ideXlab platform.
-
hiv 1 nef induced Secretion of the proinflammatory protease tace into extracellular vesicles is mediated by raf 1 and can be suppressed by clinical Protein kinase inhibitors
Journal of Virology, 2021Co-Authors: Zhe Zhao, Riku Fagerlund, Andreas Baur, Kalle SakselaAbstract:Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an Unconventional Protein Secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE Secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger the Secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of Unconventional Protein Secretion and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10% to 40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EVs), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here, we show that Nef promotes uploading of TACE into EVs by triggering Unconventional Secretion via activation of the Hck/Raf/mitogen-activated Protein kinase (MAPK) cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation and could thus provide a novel strategy for treating HIV-associated immune activation.
-
hiv 1 nef induced Secretion of the proinflammatory protease tace into extracellularvesicles is mediated by raf 1 and can be suppressed by clinical Protein kinase inhibitors
Journal of Virology, 2021Co-Authors: Zhe Zhao, Riku Fagerlund, Andreas Baur, Kalle SakselaAbstract:Chronic immune activation is an important driver of HIV-1 pathogenesis, and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EV) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase Hck by HIV-1 Nef can trigger the packaging of TACE into EVs via an Unconventional Protein Secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and SIV Nef alleles we now show that the capacity to promote TACE Secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger Secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of Unconventional Protein Secretion, and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of HIV-1 infection, and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10-40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EV), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here we show that Nef promotes uploading of TACE into EVs by triggering Unconventional Secretion via activation of the Hck/Raf/MAPK kinase cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation, and could thus provide a novel strategy for treating HIV-associated immune activation.
Vivek Malhotra - One of the best experts on this subject based on the ideXlab platform.
-
building new compartments for Unconventional Protein Secretion from the early and late golgi membranes
bioRxiv, 2021Co-Authors: Amy J. Curwin, Nathalie Brouwers, Akihiko Nakano, Kazuo Kurokawa, Vivek MalhotraAbstract:CUPS, a compartment for Unconventional Secretion of signal sequence lacking Proteins, is built during starvation. CUPS, lacking the Golgi specific glycosyltransferases, form by COPI independent extraction of membranes from the early Golgi cisterna, require PI4P for their biogenesis and PI3P for stability. We now show that a PI4P effector Drs2 of the trans-Golgi network, relocates to a new compartment monikered TCUPS because it touches CUPS. Although localized to TCUPS, Drs2 is required for CUPS formation specifically by interacting with Rcy1, and this process is essential for Unconventional Secretion. Visualizing cells by 4D SCLIM technology revealed that tubules emanating from TCUPS are often collared by CUPS and severed. Incidentally, while CUPS are stable, TCUPS are vesiculated at late stages of starvation. This mirrors the dynamics of the early and late Golgi during conventional Protein Secretion. TCUPS and CUPS thus emerge as the functional equivalent of early and late Golgi of the conventional secretory pathway, thus representing key compartments in Unconventional Secretion.
-
Unconventional Protein Secretion triggered by nutrient starvation.
Seminars in cell & developmental biology, 2018Co-Authors: David Cruz-garcia, Vivek Malhotra, Amy J. CurwinAbstract:It is usually assumed that eukaryotic cells secrete only Proteins that contain a signal sequence for Sec61 mediated translocation into the lumen of endoplasmic reticulum (ER). Surprisingly however, many Proteins, such as superoxide dismutase (SOD)1, acyl-CoA binding Protein (Acb1), interleukin 1β, fibroblast growth factor 2 and the adipokine Unpaired2, to name a few, are secreted even though they lack a signal sequence. The discovery that these Proteins are secreted has presented a new challenge and we describe here a common pathway by which SOD1 and Acb1 are specifically secreted upon nutrient starvation. Their Secretion follows a type III Unconventional pathway, requiring the exposure of a di-acidic motif, which we propose promotes their capture into a membrane compartment called CUPS (compartment for Unconventional Protein Secretion). We suggest that CUPS, composed of membranes derived from the Golgi apparatus and endosomes, serves as a major sorting station prior to release of SOD1 and Acb1 into the extracellular space. The trafficking of these signal sequence lacking Proteins therefore has functional similarities to conventional Protein Secretion in that they rely on membrane bounded compartments for their sorting and transport, but bypass the need of Sec61 for translocating into the ER and COPII and COPI for their intracellular transfers. This review is part of a Special Issue of SCDB on "Unconventional Protein Secretion" edited by Walter Nickel and Catherine Rabouille.
-
a di acidic motif targets cytoplasmic Proteins for Unconventional Protein Secretion
bioRxiv, 2017Co-Authors: David Cruzgarcia, Nathalie Brouwers, Amy J. Curwin, Juan M Duran, Vivek MalhotraAbstract:We previously reported that Acb1, a cytoplasmic Protein in Saccharomyces cerevisiae that cannot enter the endoplasmic reticulum (ER), was secreted upon nutrient starvation by a Vps4 independent, but ESCRT-I, -II and -III and Grh1 dependent pathway (Curwin et al., 2016). Here, we report that the same conditions result in Secretion of another signal sequence lacking Protein, superoxide dismutase 1 (SOD1). Similar to Acb1, SOD1 export requires Grh1 and a subset of ESCRT components. Importantly, our analysis reveals the existence of a conserved di-acidic motif (Asp-Glu) in SOD1 and Acb1 that is required for their respective export. This sequence is different from the di-acidic motif (Asp-X-Glu) necessary for export of transmembrane Proteins from the ER. We propose that the Asp-Glu sequence acts as a targeting motif for the entry of SOD1 and Acb1, and likely many other Proteins, upon nutrient starvation into a common albeit ER-Golgi independent pathway of Secretion.
-
escrt iii drives the final stages of cups maturation for Unconventional Protein Secretion
eLife, 2016Co-Authors: Amy J. Curwin, Vivek Malhotra, Nathalie Brouwers, Manuel Alonso Y Adell, David Teis, Gabriele Turacchio, Seetharaman Parashuraman, Paolo RonchiAbstract:Cells produce thousands of different Proteins with a variety of different roles in the body. Some Proteins, for example the hormone insulin, perform roles outside of the cell and are released from cells in a process that has several stages. In the first step, newly-made insulin and many other “secretory” Proteins enter a compartment called the endoplasmic reticulum. Once inside, these Proteins can then be loaded into other compartments and transported to the edge of the cell. There is another class of secretory Proteins that are released from the cell without first entering the endoplasmic reticulum, in a process termed “Unconventional Protein Secretion”. A Protein called Acb1 is released from yeast cells in this manner. Previous research identified a compartment that might be involved in this process. However, it is not clear how this compartment (named CUPS) forms, and what role it plays in Unconventional Protein Secretion. Curwin et al. investigated how CUPS form in yeast cells, and whether the compartment contains Acb1 Proteins. The experiments reveal that after CUPS form they need to mature into a form that is involved in the release of Acb1 Proteins from the cell. This maturation process involves some, but not all, of the same genes as those involved in producing another type of compartment in cells called a multivesicular body. Acb1 is only found in the mature CUPS and multivesicular bodies are not involved in the release of this Protein from the cell. Curwin et al.’s findings shed some light on how Acb1 and other secretory Proteins can be released from cells without involving the endoplasmic reticulum. Future challenges are to reveal how CUPS capture cargo and find out how Acb1 leaves the CUPS to exit the cell.
-
Unconventional Protein Secretion: an evolving mechanism
The EMBO journal, 2013Co-Authors: Vivek MalhotraAbstract:The process by which Proteins are secreted without entering the classical endoplasmic reticulum (ER)–Golgi complex pathway, in eukaryotic cells, is conveniently called Unconventional Protein Secretion. Recent studies on one such Protein called Acb1 have revealed a number of components involved in its Secretion. Interestingly, conditions that promote the Secretion of Acb1 trigger the biogenesis of a new compartment called CUPS (Compartment for Unconventional Protein Secretion). CUPS form near the ER exit site but lack ER-specific Proteins. Other Proteins that share some of the features common with the Secretion of Acb1 are interleukin-1β and tissue transglutaminase. Here I will review recent advances made in the field and propose a new model for Unconventional Protein Secretion.
Hans Dietmar Beer - One of the best experts on this subject based on the ideXlab platform.
-
human primary keratinocytes as a tool for the analysis of caspase 1 dependent Unconventional Protein Secretion
Methods of Molecular Biology, 2016Co-Authors: Gerhard E Strittmatter, Martha Garstkiewicz, Jennifer Sand, Serena Grossi, Hans Dietmar BeerAbstract:Inflammasomes comprise a group of Protein complexes, which activate the protease caspase-1 upon sensing a variety of stress factors. Active caspase-1 in turn cleaves and thereby activates the pro-inflammatory cytokines prointerleukin (IL)-1β and -18, and induces Unconventional Protein Secretion (UPS) of mature IL-1β, IL-18, as well as of many other Proteins involved in and required for induction of inflammation. Human primary keratinocytes (HPKs) represent epithelial cells able to activate caspase-1 in an inflammasome-dependent manner upon irradiation with a physiological dose of ultraviolet B (UVB) light. Here, we describe the isolation of keratinocytes from human skin, their cultivation, and induction of caspase-1-dependent UPS upon UVB irradiation as well as its siRNA- and chemical-mediated inhibition. In contrast to inflammasome activation of professional immune cells, UVB-irradiated HPKs represent a robust and physiological cell culture system for the analysis of UPS induced by active caspase-1.
-
caspase 4 is required for activation of inflammasomes
Journal of Immunology, 2012Co-Authors: Gabriel Sollberger, Gerhard E Strittmatter, Magdalena Kistowska, Lars E French, Hans Dietmar BeerAbstract:IL-1β and IL-18 are crucial regulators of inflammation and immunity. Both cytokines are initially expressed as inactive precursors, which require processing by the protease caspase-1 for biological activity. Caspase-1 itself is activated in different innate immune complexes called inflammasomes. In addition, caspase-1 activity regulates Unconventional Protein Secretion of many other Proteins involved in inflammation and repair. Human caspase-4 is a poorly characterized member of the caspase family, which is supposed to be involved in endoplasmic reticulum stress-induced apoptosis. However, its gene is located on the same locus as the caspase-1 gene, which raises the possibility that caspase-4 plays a role in inflammation. In this study, we show that caspase-4 expression is required for UVB-induced activation of proIL-1β and for Unconventional Protein Secretion by skin-derived keratinocytes. These processes require expression of the nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 inflammasome, and caspase-4 physically interacts with its central molecule caspase-1. As the active site of caspase-4 is required for activation of caspase-1, the latter most likely represents a substrate of caspase-4. Caspase-4 expression is also essential for efficient nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 and for absent in melanoma 2 inflammasome-dependent proIL-1β activation in macrophages. These results demonstrate an important role of caspase-4 in inflammation and innate immunity through activation of caspase-1. Therefore, caspase-4 represents a novel target for the treatment of (auto)inflammatory diseases.
-
active caspase 1 is a regulator of Unconventional Protein Secretion
Cell, 2008Co-Authors: Martin Keller, Andreas Ruegg, Sabine Werner, Hans Dietmar BeerAbstract:Summary Mammalian cells export most Proteins by the endoplasmic reticulum/Golgi-dependent pathway. However, some Proteins are secreted via Unconventional, poorly understood mechanisms. The latter include the proinflammatory cytokines interleukin(IL)-1β, IL-18, and IL-33, which require activation by caspase-1 for biological activity. Caspase-1 itself is activated by innate immune complexes, the inflammasomes. Here we show that Secretion of the leaderless Proteins proIL-1α, caspase-1, and fibroblast growth factor (FGF)-2 depends on caspase-1 activity. Although proIL-1α and FGF-2 are not substrates of the protease, we demonstrated their physical interaction. Secretome analysis using iTRAQ proteomics revealed caspase-1-mediated Secretion of other leaderless Proteins with known or unknown extracellular functions. Strikingly, many of these Proteins are involved in inflammation, cytoprotection, or tissue repair. These results provide evidence for an important role of caspase-1 in Unconventional Protein Secretion. By this mechanism, stress-induced activation of caspase-1 directly links inflammation to cytoprotection, cell survival, and regenerative processes.
