Secretory lysosomes of mouse mast cells store and exocytose active caspase‐3 in a strictly granzyme B dependent manner

Zorn, Carolin N.; Pardo, Julián; Martin, Praxedis; Kuhny, Marcel; Simon, Markus M.; Huber, Michael

doi:10.1002/eji.201343941

Cited by 17 publications

(6 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fact that cleavage of Tau by caspase-3 was not necessary for its secretion by VAMP8 prompted us to examine the possibility that Tau could be extracellularly cleaved by caspase-3. Indeed, caspase-3 was previously shown to be secreted by cells ( Garcia-Faroldi et al, 2013 ; Zorn et al, 2013 ). We examined the amount of total caspase-3 and cleaved caspase-3 in the medium.…”

Section: Resultsmentioning

confidence: 99%

“…Active caspase-3 released upon VAMP8 overexpression seemed to be functional as indicated by the cleavage of rTau. In a previous study, extracellular caspase-3 released by mouse mast cells through secretory lysosomes was reported to be able to cleave interleukin-33 ( Zorn et al, 2013 ). It was proposed that extracellular active caspase-3 could be involved in the processing of cytokines and thereby contributed to the inflammatory response ( Garcia-Faroldi et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Pilliod

Gélinas-Faucher

Leclerc

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

In Alzheimer’s disease, Tau, a microtubule-associated protein, becomes hyperphosphorylated, detaches from microtubules, and accumulates in the somato-dendritic compartment where it forms insoluble aggregates. Tau also accumulates in the CSF of patients indicating that it is released by neurons. Consistent with this, several laboratories including ours have shown that Tau is secreted by neurons through unconventional secretory pathways. Recently, we reported that VAMP8, an R-SNARE found on late endosomes, increased Tau secretion and that secreted Tau was cleaved at the C-terminal. In the present study, we examined whether the increase of Tau secretion by VAMP8 affected its intra- and extracellular cleavage. Upon VAMP8 overexpression, an increase of Tau cleaved by caspase-3 in the cell lysate and medium was observed. This was correlated to an increase of active caspase-3 in the cell lysate and medium. Using a Tau mutant not cleavable by caspase-3, we demonstrated that Tau cleavage by caspase-3 was not necessary for its secretion upon VAMP8 overexpression. By adding recombinant Tau to the culture medium, we demonstrated that extracellular Tau cleavage by caspase-3 could occur because of the release of active caspase-3, which was the highest when VAMP8 was overexpressed. When cleavage of Tau by caspase-3 was prevented by using a non-cleavable mutant, secreted Tau was still cleaved at the C-terminal, the asparagine N410 contributing to it. Lastly, we demonstrated that N-terminal of Tau regulated the secretion pattern of a Tau fragment containing the microtubule-binding domain and the C-terminal of Tau upon VAMP8 overexpression. Collectively, the above observations indicate that VAMP8 overexpression affects the intra- and extracellular cleavage pattern of Tau.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Pilliod

Gélinas-Faucher

Leclerc

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…This may be due in part to the ability of GzmB to induce apoptosis via multiple independent pathways ( Chowdhury and Lieberman, 2008 ; Martinvalet, 2015 ). It has been proposed that pro-caspase-3 is also stored and activated in a granzyme B-dependent manner in mast cell secretory granules ( Garcia-Faroldi et al, 2013 ; Zorn et al, 2013 ). While we cannot exclude the possibility that granule caspase-3 contributes to mast cell death, our data support the view that caspase-3 activation classically occurs in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Granule Leakage Induces Cell-Intrinsic, Granzyme B-Mediated Apoptosis in Mast Cells

Burgener

Brügger

Leborgne

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Mast cells are multifunctional immune cells scattered in tissues near blood vessels and mucosal surfaces where they mediate important reactions against parasites and contribute to the pathogenesis of allergic reactions. Serine proteases released from secretory granules upon mast cell activation contribute to these functions by modulating cytokine activity, platelet activation and proteolytic neutralization of toxins. The forced release of granule proteases into the cytosol of mast cells to induce cell suicide has recently been proposed as a therapeutic approach to reduce mast cell numbers in allergic diseases, but the molecular pathways involved in granule-mediated mast cell suicide are incompletely defined. To identify intrinsic granule proteases that can cause mast cell death, we used mice deficient in cytosolic serine protease inhibitors and their respective target proteases. We found that deficiency in Serpinb1a, Serpinb6a, and Serpinb9a or in their target proteases did not alter the kinetics of apoptosis induced by growth factor deprivation in vitro or the number of peritoneal mast cells in vivo. The serine protease cathepsin G induced marginal cell death upon mast cell granule permeabilization only when its inhibitors Serpinb1a or Serpinb6a were deleted. In contrast, the serine protease granzyme B was essential for driving apoptosis in mast cells. On granule permeabilization, granzyme B was required for caspase-3 processing and cell death. Moreover, cytosolic granzyme B inhibitor Serpinb9a prevented caspase-3 processing and mast cell death in a granzyme B-dependent manner. Together, our findings demonstrate that cytosolic serpins provide an inhibitory shield preventing granule protease-induced mast cell apoptosis, and that the granzyme B-Serpinb9a-caspase-3 axis is critical in mast cell survival and could be targeted in the context of allergic diseases.

show abstract

“…The enzyme was located in subcellular fractions containing secretory granulelocalized proteases and rapidly released into the cytosolic compartment after permeabilization of the secretory granules upon mast cell activation. 101,102…”

Section: Caspases In Monocyte Differentiation Into Macrophagesmentioning

confidence: 99%

Non-apoptotic functions of caspases in myeloid cell differentiation

et al. 2017

View full text Add to dashboard Cite

Subtle caspase activation is associated with the differentiation of several myeloid lineages. A tightly orchestrated dance between caspase-3 activation and the chaperone HSP70 that migrates to the nucleus to protect the master regulator GATA-1 from cleavage transiently occurs in basophilic erythroblasts and may prepare nucleus and organelle expel that occurs at the terminal phase of erythroid differentiation. A spatially restricted activation of caspase-3 occurs in maturing megakaryocytes to promote proplatelet maturation and platelet shedding in the bloodstream. In a situation of acute platelet need, caspase-3 could be activated in response to IL-1α and promote megakaryocyte rupture. In peripheral blood monocytes, colony-stimulating factor-1 provokes the formation of a molecular platform in which caspase-8 is activated, which downregulates nuclear factor-kappa B (NF-κB) activity and activates downstream caspases whose target fragments such as those generated by nucleophosmin (NPM1) cleavage contribute to the generation of resting macrophages. Human monocytes secrete mature IL-1β in response to lipopolysaccharide through an alternative inflammasome activation that involves caspase-8, a pathway that does not lead to cell death. Finally, active caspase-3 is part of the proteases contained in secretory granules of mast cells. Many questions remain on how these proteases are activated in myeloid cell lineages, which target proteins are cleaved, whereas other are protected from proteolysis, the precise role of cleaved proteins in cell differentiation and functions, and the link between these non-apoptotic functions of caspases and the death of these diverse cell types. Better understanding of these functions may generate therapeutic strategies to control cytopenias or modulate myeloid cell functions in various pathological situations.

show abstract

Secretory lysosomes of mouse mast cells store and exocytose active caspase‐3 in a strictly granzyme B dependent manner

Cited by 17 publications

References 42 publications

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Granule Leakage Induces Cell-Intrinsic, Granzyme B-Mediated Apoptosis in Mast Cells

Non-apoptotic functions of caspases in myeloid cell differentiation

Contact Info

Product

Resources

About