Secretory lysosomes

Blott, Emma J.; Griffiths, Gillian M.

doi:10.1038/nrm732

Cited by 674 publications

(592 citation statements)

References 93 publications

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“…The small GTPases Rab27a and Rab27b were considered to be candidate molecules involved in stimulation-dependent RANKL release because they are reported to be involved in the stimulation-dependent release of contents from lysosomal organelles in many other kinds of cells. (32,43,44) In osteoblastic cells, suppression of either Rab27a or Rab27b inhibited stimulation-dependent RANKL release ( Figs. 1 and 2).…”

Section: Discussionmentioning

confidence: 99%

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Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

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The quantity of the receptor activator of NF-kB ligand (RANKL) expressed at the cell surface of osteoblastic cells is an important factor regulating osteoclast activation. Previously, RANKL was found to be localized to secretory lysosomes in osteoblastic cells and to translocate to the cell surface in response to stimulation with RANK-Fc-conjugated beads. However, the in vivo significance of stimulation-dependent RANKL release has not been elucidated. In this study we show that small GTPases Rab27a and Rab27b are involved in the stimulation-dependent RANKL release pathway in osteoblastic cells. Suppression of either Rab27a or Rab27b resulted in a marked reduction in RANKL release after stimulation. Slp4-a, Slp5, and Munc13-4 acted as effector molecules that coordinated Rab27a/b activity in this pathway. Suppression of Rab27a/b or these effector molecules did not inhibit accumulation of RANKL in lysosomal vesicles around the stimulated sites but did inhibit the fusion of these vesicles to the plasma membrane. In osteoblastic cells, suppression of the effector molecules resulted in reduced osteoclastogenic ability. Furthermore, Jinx mice, which lack a functional Munc13-4 gene, exhibited a phenotype characterized by increased bone volume near the tibial metaphysis caused by low bone resorptive activity. In conclusion, stimulation-dependent RANKL release is mediated by Rab27a/b and their effector molecules, and this mechanism may be important for osteoclast activation in vivo. ß

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Section: Discussionmentioning

confidence: 99%

“…(28,44) The regulation of RANKL in osteoblastic cells is similar to that of FasL in cytotoxic Tlymphocytes; however, there are also some differences. (24,(46)(47)(48)(49) Both Rab27a and Rab27b are involved in stimulation-dependent RANKL release in osteoblastic cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

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“…Another critical aspect may be that the recycling of CD63, CD107a and FasL by endocytosis and thus the intracellular localization may be different under these distinct conditions. Whereas CD63 and CD107a are known to be transiently secreted to the plasma membrane from where they are recycled to the secretory lysosomes by endocytosis, 33 FasL is directly targeted from the trans-Golgi network to the secretory lysosomes. 8 Depending on the stage of FasL production and recycling of classical granule markers a differential subcellular localization may result, likely also affecting the mechanism of activation-induced release of the different granule content.…”

Section: Discussionmentioning

confidence: 99%

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

et al. 2008

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Fas (CD95/Apo-1) ligand is a potent inducer of apoptosis and one of the major killing effector mechanisms of cytotoxic T cells. Thus, Fas ligand activity has to be tightly regulated, involving various transcriptional and post-transcriptional processes. For example, preformed Fas ligand is stored in secretory lysosomes of activated T cells, and rapidly released by degranulation upon reactivation. In this study, we analyzed the minimal requirements for activation-induced degranulation of Fas ligand. T cell receptor activation can be mimicked by calcium ionophore and phorbol ester. Unexpectedly, we found that stimulation with phorbol ester alone is sufficient to trigger Fas ligand release, whereas calcium ionophore is neither sufficient nor necessary. The relevance of this process was confirmed in primary CD4 þ and CD8 þ T cells and NK cells. Although the activation of protein kinase(s) was absolutely required for Fas ligand degranulation, protein kinase C or A were not involved. Previous reports have shown that preformed Fas ligand co-localizes with other markers of cytolytic granules. We found, however, that the activationinduced degranulation of Fas ligand has distinct requirements and involves different mechanisms than those of the granule markers CD63 and CD107a/Lamp-1. We conclude that activation-induced degranulation of Fas ligand in cytotoxic lymphocytes is differently regulated than other classical cytotoxic granule proteins.

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“…Another example of P2X7R-stimulated exocytosis is the fusion of the so-called secretory lysosomes with the plasma membrane triggered by extracellular ATP which occurs concurrently with the release of cytokine IL-1β and its converting enzyme caspase-1 in murine macrophages [40] and human monocytes [39]. Secretory lysosomes represent a specialized subtype of lysosomes that predominantly are expressed in hematopoietic cells [103]. These include the histamine-and serotonin-containing dense granules of mast cells, the perforin-and granzymecontaining granules of cytolytic T lymphocytes, and the major basic protein granules of eosinophils.…”

Section: P2x7r-induced Exocytosis Of Secretory Lysosomesmentioning

confidence: 99%

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

Dubyak

2009

Purinergic Signalling

108

101

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Activation of the P2X7 receptor (P2X7R) triggers a remarkably diverse array of membrane trafficking responses in leukocytes and epithelial cells. These responses result in altered profiles of cell surface lipid and protein composition that can modulate the direct interactions of P2X7R-expressing cells with other cell types in the circulation, in blood vessels, at epithelial barriers, or within sites of immune and inflammatory activation. Additionally, these responses can result in the release of bioactive proteins, lipids, and large membrane complexes into extracellular compartments for remote communication between P2X7R-expressing cells and other cells that amplify or modulate inflammation, immunity, and responses to tissue damages. This review will discuss P2X7R-mediated effects on membrane composition and trafficking in the plasma membrane (PM) and intracellular organelles, as well as actions of P2X7R in controlling various modes of nonclassical secretion. It will review P2X7R regulation of: (1) phosphatidylserine distribution in the PM outer leaflet; (2) shedding of PM surface proteins; (3) release of PM-derived microvesicles or microparticles; (4) PM blebbing; (5) cell-cell fusion resulting in formation of multinucleate cells; (6) phagosome maturation and fusion with lysosomes; (7) permeability of endosomes with internalized pathogen-associated molecular patterns; (8) permeability/integrity of mitochondria; (9) exocytosis of secretory lysosomes; and (10) release of exosomes from multivesicular bodies.

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Secretory lysosomes

Cited by 674 publications

References 93 publications

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

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