Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation

Zuccato, Elisabetta; Blott, Emma J.; Holt, Oliver J.; Sigismund, Sara; Shaw, Michael K.; Bossi, Giovanna; Griffiths, Gillian M.

doi:10.1242/jcs.03315

Cited by 105 publications

(90 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mechanisms that control TRAIL translocation from the intracellular pools to the cell surface [51] are currently unknown and are the subject of continuing investigation. Monoubiquitination was shown to play an important role in the protein translocation of Fas Ligand [52]. However, protein modifications of TRAIL linked with its intracellular trafficking are still incompletely investigated.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

View full text Add to dashboard Cite

Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

show abstract

Section: Discussionmentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…These include the Src-like kinases Fyn, Lyn, and Fgr and the adaptor proteins Nck, Grb2 and PSTPIP. 28,[35][36][37][38][39] Of interest is the recently described interaction between Nck and FasL, as Nck likely links preformed and granule-stored FasL to WASP and the cytoskeleton. 38 In agreement with our observation that PMA-induced FasL degranulation was latrunculin B-sensitive it was found that the delivery of FasL to the immunological synapse was dependent on actin filament formation.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…In the second, FasL is anchored to intracellular membrane microvesicles, where it is stored until expressed on the cell surface in response to physiological stimuli. The last corresponds to a soluble FasL, which is generated by degradation of the membranous shape (during the first minutes of expression) due to the activity of a metalloprotease matrix whose function is to catalyze the degradation of extracellular matrix proteins (108)(109)(110)(111). The soluble FasL molecule has either pro-apoptotic or antiapoptotic properties since soluble FasL is an inefficient homotrimer binding to Fas.…”

Section: Fas-fasl Intercellular Linkage-mediated Pathwaymentioning

confidence: 99%

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

et al. 2009

View full text Add to dashboard Cite

One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8 + T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lytic molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis. Cellular & Molecular Immunology. 2009;6(1):15-25.

show abstract

Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation

Cited by 105 publications

References 31 publications

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

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

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

Contact Info

Product

Resources

About