Sanquin Research and Landsteiner Laboratory AMC UvA

Amsterdam, Netherlands

Sanquin Research and Landsteiner Laboratory AMC UvA

Amsterdam, Netherlands
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Horos R.,Erasmus University Rotterdam | Horos R.,European Molecular Biology Laboratory | von Lindern M.,Erasmus University Rotterdam | von Lindern M.,Sanquin Research and Landsteiner Laboratory AMC UvA
British Journal of Haematology | Year: 2012

Diamond Blackfan Anaemia (DBA) is a rare congenital pure red cell aplasia that may be associated with facio-skeletal developmental defects. The disease is caused by mutations in one of at least ten ribosomal proteins, which results in haploinsufficiency and an imbalance between the synthesis of rRNA and ribosomal proteins during ribosome biogenesis. Such imbalance results in stabilization and activation of the tumour suppressor gene TP53. The loss of ribosomes also results in reduced mRNA translation capacity, and may affect translation of specific erythroid transcripts more than average. The contribution of these two mechanisms to impaired erythropoiesis is discussed. The most effective and relatively safe therapy is treatment with glucocorticoid hormone, but responsiveness differs between patients. The molecular and cellular mechanisms involved in treatment are discussed in the context of DBA. © 2012 Blackwell Publishing Ltd.


Jongsma M.L.M.,Netherlands Cancer Institute | Jongsma M.L.M.,Sanquin Research and Landsteiner Laboratory AMC UvA | Berlin I.,Netherlands Cancer Institute | Wijdeven R.H.M.,Netherlands Cancer Institute | And 9 more authors.
Cell | Year: 2016

Through a network of progressively maturing vesicles, the endosomal system connects the cell's interior with extracellular space. Intriguingly, this network exhibits a bilateral architecture, comprised of a relatively immobile perinuclear vesicle “cloud” and a highly dynamic peripheral contingent. How this spatiotemporal organization is achieved and what function(s) it curates is unclear. Here, we reveal the endoplasmic reticulum (ER)-located ubiquitin ligase Ring finger protein 26 (RNF26) as the global architect of the entire endosomal system, including the trans-Golgi network (TGN). To specify perinuclear vesicle coordinates, catalytically competent RNF26 recruits and ubiquitinates the scaffold p62/sequestosome 1 (p62/SQSTM1), in turn attracting ubiquitin-binding domains (UBDs) of various vesicle adaptors. Consequently, RNF26 restrains fast transport of diverse vesicles through a common molecular mechanism operating at the ER membrane, until the deubiquitinating enzyme USP15 opposes RNF26 activity to allow vesicle release into the cell's periphery. By drawing the endosomal system's architecture, RNF26 orchestrates endosomal maturation and trafficking of cargoes, including signaling receptors, in space and time. © 2016 The Author(s)


PubMed | Leiden University, Sanquin Research and Landsteiner Laboratory AMC UvA and Netherlands Cancer Institute
Type: Journal Article | Journal: Cell | Year: 2016

Through a network of progressively maturing vesicles, the endosomal system connects the cells interior with extracellular space. Intriguingly, this network exhibits a bilateral architecture, comprised of a relatively immobile perinuclear vesicle cloud and a highly dynamic peripheral contingent. How this spatiotemporal organization is achieved and what function(s) it curates is unclear. Here, we reveal the endoplasmic reticulum (ER)-located ubiquitin ligase Ring finger protein 26 (RNF26) as the global architect of the entire endosomal system, including the trans-Golgi network (TGN). To specify perinuclear vesicle coordinates, catalytically competent RNF26 recruits and ubiquitinates the scaffold p62/sequestosome 1 (p62/SQSTM1), in turn attracting ubiquitin-binding domains (UBDs) of various vesicle adaptors. Consequently, RNF26 restrains fast transport of diverse vesicles through a common molecular mechanism operating at the ER membrane, until the deubiquitinating enzyme USP15 opposes RNF26 activity to allow vesicle release into the cells periphery. Bydrawing the endosomal systems architecture, RNF26 orchestrates endosomal maturation and trafficking of cargoes, including signaling receptors, in space and time.


Koning J.J.,VU University Amsterdam | Kooij G.,VU University Amsterdam | de Vries H.E.,VU University Amsterdam | Nolte M.A.,Sanquin Research and Landsteiner Laboratory AMC UvA | Mebius R.E.,VU University Amsterdam
Frontiers in Immunology | Year: 2013

Mesenchymal stem cells (MSCs) show great therapeutic potential for the treatment of various immune mediated diseases, including Multiple Sclerosis (MS). Systemic administration of MSCs during experimental allergic encephalomyelitis (EAE), an animal model for MS, was shown to reduce the infiltration of T cells, B cells, and macrophages into the CNS. Whether endogenous MSCs are mobilized and potentially modulate the severity of disease is not known. Here we show that during the acute phase of EAE, MSCs numbers in the bone marrow were severely reduced, which restored to control levels during the progressive phase of the disease. The number of bone marrow MSCs inversely correlated with the number of both CD4 and CD8 T cells present in the bone marrow indicating a link between activated T cells and MSC mobilization. Analysis of CD70-transgenic mice, which have a constitutively activated immune system and elevated number of activated T cells in the bone marrow, showed severely reduced number of bone marrow MSCs. Transfer of T cells that were activated through their CD27 receptor reduced the number of bone marrow MSCs dependent on IFN-y. These data provide a mechanism by which MSCs can be mobilized from the bone marrow in order to contribute to tissue repair at a distant location. © 2013 Koning, Kooij, de Vries, Nolte and Mebius.


De Bruin A.M.,University of Amsterdam | Voermans C.,Sanquin Research and Landsteiner Laboratory AMC UvA | Nolte M.A.,Sanquin Research and Landsteiner Laboratory AMC UvA
Blood | Year: 2014

The proinflammatory cytokine interferon-γ (IFN-γ) is well known for its important role in innate and adaptive immunity against intracellular infections and for tumor control. Yet, it has become clear that IFN-γ also has a strong impact on bone marrow (BM) output during inflammation, as it affects the differentiation of most hematopoietic progenitor cells. Here, we review the impact of IFN-γ on hematopoiesis, including the function of hematopoietic stem cells (HSCs) and more downstream progenitors. We discuss which hematopoietic lineages are functionally modulated by IFN-γ and through which underlying molecular mechanism(s). We propose the novel concept that IFN-γ acts through upregulation of suppressor of cytokine signaling molecules, which impairs signaling of several cytokine receptors. IFN-γ has also gained clinical interest from different angles, and we discuss how chronic IFN-γ production can lead to the development of anemia and BM failure and how it is involved in malignant hematopoiesis. Overall, this review illustrates the wide-ranging effect of IFN-γ on the (patho-)physiological processes in the BM. © 2014 by The American Society of Hematology.


Wijdeven R.H.,Netherlands Cancer Institute | Jongsma M.L.M.,Sanquin Research and Landsteiner Laboratory AMC UvA | Neefjes J.,Netherlands Cancer Institute | Berlin I.,Netherlands Cancer Institute
BioEssays | Year: 2015

Endosomes shuttle select cargoes between cellular compartments and, in doing so, maintain intracellular homeostasis and enable interactions with the extracellular space. Directionality of endosomal transport critically impinges on cargo fate, as retrograde (microtubule minus-end directed) traffic delivers vesicle contents to the lysosome for proteolysis, while the opposing anterograde (plus-end directed) movement promotes recycling and secretion. Intriguingly, the endoplasmic reticulum (ER) is emerging as a key player in spatiotemporal control of late endosome and lysosome transport, through the establishment of physical contacts with these organelles. Earlier studies have described how minus-end-directed motor proteins become discharged from vesicles engaged at such contact sites. Now, Raiborg et al. implicate ER-mediated interactions, induced by protrudin, in loading plus-end-directed motor kinesin-1 onto endosomes, thereby stimulating their transport toward the cell's periphery. In this review, we recast the prevailing concepts on bidirectional late endosome transport and discuss the emerging paradigm of inter-compartmental regulation from the ER-endosome interface viewpoint. © 2015 WILEY Periodicals, Inc.


Nolte M.A.,Sanquin Research and Landsteiner Laboratory AMC UvA | van Lier R.A.W.,Sanquin Research and Landsteiner Laboratory AMC UvA
European Journal of Immunology | Year: 2013

CD40-CD40L interactions are important for both antigen-dependent B-cell differentiation and effector and memory T-cell formation. The prevailing view is that CD40L is expressed on activated CD4+ T cells, which enables them to provide help to high-affinity B cells in GCs and to license DCs for efficient induction of CD8+ T-cell responses. Interestingly, CD8+ T cells themselves can also express CD40L and, in this issue of the European Journal of Immunology, Thiel and colleagues [Eur. J. Immunol. 2013. 43: 1511-1517] show that CD40L expression on these cells can be part of a self-sustaining feed-forward loop, in which expression of CD40L is induced by IL-12 and TCR signaling. This provides a paradigm shift in our thinking about the requirements of effector CD8+ T-cell development and the role herein of CD4+ T cells to provide help in this process. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Vieira Braga F.A.,Sanquin Research and Landsteiner Laboratory AMC UvA | Hertoghs K.M.L.,Sanquin Research and Landsteiner Laboratory AMC UvA | van Lier R.A.W.,Sanquin Research and Landsteiner Laboratory AMC UvA | van Gisbergen K.P.J.M.,Sanquin Research and Landsteiner Laboratory AMC UvA
European Journal of Immunology | Year: 2015

CD8+ T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8+ T-cell response is characterized by the accumulation of terminally differentiated effector cells that have downregulated the costimulatory molecules CD27 and CD28. These HCMV-specific CD8+ T cells maintain high levels of cytotoxic molecules such as granzyme B and rapidly produce the inflammatory cytokine IFN-γ upon activation. Remarkably, HCMV-specific CD8+ T cells are able to persist long term as fully functional effector cells, suggesting a unique differentiation pathway that is distinct from the formation of memory CD8+ T cells after infection with acute viruses. In this review, we aim to highlight the most recent developments in HCMV-specific CD8+ T-cell differentiation, maintenance, tissue distribution, metabolism and function. HCMV also induces the differentiation of effector CD4+ T cells and NK cells, which share characteristics with HCMV-specific CD8+ T cells. We propose that the overlap in differentiation of NK cells, CD4+ and CD8+ T cells after HCMV infection may be regulated by a shared transcriptional machinery. A better understanding of the molecular framework of HCMV-specific CD8+ T-cell responses may benefit vaccine design, as these cells uniquely combine the capacity to rapidly respond to infection with long-term survival. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Sanquin Research and Landsteiner Laboratory AMC UvA and Netherlands Cancer Institute
Type: Journal Article | Journal: BioEssays : news and reviews in molecular, cellular and developmental biology | Year: 2015

Endosomes shuttle select cargoes between cellular compartments and, in doing so, maintain intracellular homeostasis and enable interactions with the extracellular space. Directionality of endosomal transport critically impinges on cargo fate, as retrograde (microtubule minus-end directed) traffic delivers vesicle contents to the lysosome for proteolysis, while the opposing anterograde (plus-end directed) movement promotes recycling and secretion. Intriguingly, the endoplasmic reticulum (ER) is emerging as a key player in spatiotemporal control of late endosome and lysosome transport, through the establishment of physical contacts with these organelles. Earlier studies have described how minus-end-directed motor proteins become discharged from vesicles engaged at such contact sites. Now, Raiborg et al. implicate ER-mediated interactions, induced by protrudin, in loading plus-end-directed motor kinesin-1 onto endosomes, thereby stimulating their transport toward the cells periphery. In this review, we recast the prevailing concepts on bidirectional late endosome transport and discuss the emerging paradigm of inter-compartmental regulation from the ER-endosome interface viewpoint.


PubMed | Sanquin Research and Landsteiner Laboratory AMC UvA
Type: Journal Article | Journal: European journal of immunology | Year: 2015

CD8(+) Tcells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8(+) T-cell response is characterized by the accumulation of terminally differentiated effector cells that have downregulated the costimulatory molecules CD27 and CD28. These HCMV-specific CD8(+) Tcells maintain high levels of cytotoxic molecules such as granzyme B and rapidly produce the inflammatory cytokine IFN- upon activation. Remarkably, HCMV-specific CD8(+) Tcells are able to persist long term as fully functional effector cells, suggesting a unique differentiation pathway that is distinct from the formation of memory CD8(+) Tcells after infection with acute viruses. In this review, we aim to highlight the most recent developments in HCMV-specific CD8(+) T-cell differentiation, maintenance, tissue distribution, metabolism and function. HCMV also induces the differentiation of effector CD4(+) Tcells and NK cells, which share characteristics with HCMV-specific CD8(+) Tcells. We propose that the overlap in differentiation of NK cells, CD4(+) and CD8(+) Tcells after HCMV infection may be regulated by a shared transcriptional machinery. A better understanding of the molecular framework of HCMV-specific CD8(+) T-cell responses may benefit vaccine design, as these cells uniquely combine the capacity to rapidly respond to infection with long-term survival.

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