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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.

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.

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)

Costes L.M.M.,Tytgat Institute for Liver and Intestinal Research | Van Der Vliet J.,Tytgat Institute for Liver and Intestinal Research | Farro G.,Translational Research Center for Gastrointestinal Disorders | Matteoli G.,Translational Research Center for Gastrointestinal Disorders | And 6 more authors.
PLoS ONE | Year: 2014

Background: Postoperative ileus is characterized by a transient impairment of the gastrointestinal motility after abdominal surgery. The intestinal inflammation, triggered by handling of the intestine, is the main factor responsible for the prolonged dysmotility of the gastrointestinal tract. Secondary lymphoid organs of the intestine were identified as essential components in the dissemination of inflammation to the entire gastrointestinal tract also called field effect. The involvement of the spleen, however, remains unclear. Aim: In this study, we investigated whether the spleen responds to manipulation of the intestine and participates in the intestinal inflammation underlying postoperative ileus. Methods: Mice underwent Laparotomy (L) or Laparotomy followed by Intestinal Manipulation (IM). Twenty-four hours later, intestinal and colonic inflammation was assessed by QPCR and measurement of the intestinal transit was performed. Analysis of homeostatic chemokines in the spleen was performed by QPCR and splenic cell populations analysed by Flow Cytometry. Blockade of the egress of cells from the spleen was performed by administration of the Sphingosine-1-phosphate receptor 1 (S1P1) agonist CYM-5442 10 h after L/IM. Results: A significant decrease in splenic weight and cellularity was observed in IM mice 24 h post-surgery, a phenomenon associated with a decreased splenic expression level of the homeostatic chemokine CCL19. Splenic denervation restored the expression of CCL19 and partially prevented the reduction of splenocytes in IM mice. Treatment with CYM-5442 prevented the egress of splenocytes but did not ameliorate the intestinal inflammation underlying postoperative ileus. Conclusions: Intestinal manipulation results in two distinct phenomena: local intestinal inflammation and a decrease in splenic cellularity. The splenic response relies on an alteration of cell trafficking in the spleen and is partially regulated by the splenic nerve. The spleen however does not participate in the intestinal inflammation during POI. © 2014 Costes et al.

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.

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