Life Sciences Research for Lifelong Health

Publications

The Babraham Institute Publications database contains details of all publications resulting from our research groups and scientific services.

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Title / Authors / Details Open Access Download

Who plays the ferryman: ATG2 channels lipids into the forming autophagosome.
Ktistakis NT

Expansion of the autophagosomal membrane requires a mechanism to supply lipids while excluding most membrane proteins. In this issue, Valverde et al. (2019. https://doi.org/10.1083/jcb.201811139) identify ATG2, a member of the autophagy-related protein family, as a lipid transfer protein and provide important novel insights on how autophagosomes grow.

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The Journal of cell biology, , 1540-8140, , 2019

PMID: 31076453


Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ.
Swan DJ, Aschenbrenner D, Lamb CA, Chakraborty K, Clark J, Pandey S, Engelhardt KR, Chen R, Cavounidis A, Ding Y, Krasnogor N, Carey CD, Acres M, Needham S, Cant AJ, Arkwright PD, Chandra A, Okkenhaug K, Uhlig HH, Hambleton S

Haematologica, , 1592-8721, , 2019

PMID: 31073077


Open Access

MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF amplification whereas KRAS amplification promotes EMT-chemoresistance.
Sale MJ, Balmanno K, Saxena J, Ozono E, Wojdyla K, McIntyre RE, Gilley R, Woroniuk A, Howarth KD, Hughes G, Dry JR, Arends MJ, Caro P, Oxley D, Ashton S, Adams DJ, Saez-Rodriguez J, Smith PD, Cook SJ

Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF or KRAS to reinstate ERK1/2 signalling. Here we show that BRAF amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAF amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAF. p57 expression is required for loss of BRAF amplification and reversal of MEKi resistance. Thus, BRAF amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRAS amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRAS amplification.

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Nature communications, 10, 2041-1723, 2030, 2019

PMID: 31048689


FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.
Espéli M, Bashford-Rogers R, Sowerby JM, Alouche N, Wong L, Denton AE, Linterman MA, Smith KGC

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.

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Nature communications, 10, 2041-1723, 1970, 2019

PMID: 31036800


Regulation of regulatory T cells in cancer.
Stockis J, Roychoudhuri R, Halim TYF

The inflammatory response to transformed cells forms the cornerstone of natural or therapeutically-induced protective immunity to cancer. Regulatory T (Treg) cells are known for their critical role in suppressing inflammation, and therefore can antagonize effective anti-cancer immune responses. As such, Treg cells can play detrimental roles in tumour progression and in the response to both conventional and immune-based cancer therapy. Recent advances in our understanding of Treg cells reveal complex niche-specific regulatory programs and functions, which are likely to extrapolate to cancer. The regulation of Treg cells is reliant on upstream cues from haematopoietic and non-immune cells, which dictates their genetic, epigenetic, and downstream functional programmes. In this Review we will discuss how Treg cells are themselves regulated in normal and transformed tissues, and the implications of this crosstalk on tumour growth. This article is protected by copyright. All rights reserved.

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Immunology, , 1365-2567, , 2019

PMID: 31032905


Open Access

A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice.
Sendžikaitė G, Hanna CW, Stewart-Morgan KR, Ivanova E, Kelsey G

DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.

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Nature communications, 10, 2041-1723, 1884, 2019

PMID: 31015495


Open Access

Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism.
Fachi JL, Felipe JS, Pral LP, da Silva BK, Corrêa RO, de Andrade MCP, da Fonseca DM, Basso PJ, Câmara NOS, de Sales E Souza ÉL, Dos Santos Martins F, Guima SES, Thomas AM, Setubal JC, Magalhães YT, Forti FL, Candreva T, Rodrigues HG, de Jesus MB, Consonni SR, Farias ADS, Varga-Weisz P, Vinolo MAR

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.

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Cell reports, 27, 2211-1247, 750-761.e7, 2019

PMID: 30995474


Open Access

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.
Montalbán-Loro R, Lozano-Ureña A, Ito M, Krueger C, Reik W, Ferguson-Smith AC, Ferrón SR

Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N (Snrpn), contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.

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Nature communications, 10, 2041-1723, 1726, 2019

PMID: 30979904


Open Access

RNA binding proteins in hematopoiesis and hematological malignancy.
Hodson DJ, Screen M, Turner M

RNA binding proteins (RBPs) regulate fundamental processes such as differentiation and self-renewal by enabling the dynamic control of protein abundance or isoforms, or through the regulation of non-coding RNA. RBPs are increasingly appreciated as being essential for normal hematopoiesis and they are understood to play fundamental roles in hematological malignancies by acting as oncogenes or tumor suppressors. Alternative splicing has been shown to play roles in the development of specific hematopoietic lineages and sequence specific mutations in RBPs lead to dysregulated splicing in myeloid and lymphoid leukemias. RBPs that regulate translation contribute to the development and function of hematological lineages, act as nodes for the action of multiple signaling pathways and contribute to hematological malignancies. These insights broaden our mechanistic understanding of the molecular regulation of hematopoiesis and offer opportunities to develop disease biomarkers and new therapeutic modalities.

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Blood, , 1528-0020, , 2019

PMID: 30967369


Open Access

Macropinocytosis and autophagy crosstalk in nutrient scavenging.
Florey O, Overholtzer M

Adaptive strategies used by cells to scavenge and recycle essential nutrients are important for survival in nutrient-depleted environments such as cancer tissues. Autophagy and macropinocytosis are two major mechanisms that promote nutrient recycling and scavenging, which share considerable, yet poorly understood, cross-regulation. Here we review recent findings that connect these starvation response mechanisms and discuss the implications of their crosstalk. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.

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Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 374, 1471-2970, 20180154, 2019

PMID: 30967004


Open Access

A scoping review of ontologies related to human behaviour change.
Norris E, Finnerty AN, Hastings J, Stokes G, Michie S

Ontologies are classification systems specifying entities, definitions and inter-relationships for a given domain, with the potential to advance knowledge about human behaviour change. A scoping review was conducted to: (1) identify what ontologies exist related to human behaviour change, (2) describe the methods used to develop these ontologies and (3) assess the quality of identified ontologies. Using a systematic search, 2,303 papers were identified. Fifteen ontologies met the eligibility criteria for inclusion, developed in areas such as cognition, mental disease and emotions. Methods used for developing the ontologies were expert consultation, data-driven techniques and reuse of terms from existing taxonomies, terminologies and ontologies. Best practices used in ontology development and maintenance were documented. The review did not identify any ontologies representing the breadth and detail of human behaviour change. This suggests that advancing behavioural science would benefit from the development of a behaviour change intervention ontology.

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Nature human behaviour, 3, 2397-3374, 164-172, 2019

PMID: 30944444


Inborn errors of immunity: single mutations unravel mechanisms of immune disease.
Liston A, Humblet-Baron S

Immunology and cell biology, , 1440-1711, , 2019

PMID: 30942931


Translation of inhaled drug optimization strategies into clinical pharmacokinetics and pharmacodynamics using GSK2292767A, a novel inhaled PI3Kδ inhibitor.
Begg M, Edwards CD, Hamblin JN, Pifani E, Wilson R, Gilbert J, Vitulli G, Mallett D, Morrell J, Hingle MI, Uddin S, Ehtesham F, Marotti M, Harell A, Newman C, Fernando D, Clark J, Cahn A, Hessel EM

This study describes the pharmacokinetic (PK) and pharmacodynamic (PD) profile of GSK2292767A, a novel low solubility inhaled PI3Kδ inhibitor developed as an alternative to nemiralisib, which is a highly soluble inhaled inhibitor of PI3Kδ with a lung profile consistent with once-daily dosing. GSK2292767A has a similar in vitro cellular profile to nemiralisib and reduces eosinophilia in a murine PD model by 63% (n=5, p

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The Journal of pharmacology and experimental therapeutics, , 1521-0103, , 2019

PMID: 30940692


Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression.
Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, Ulas T, Papantonopoulou O, Van Eck M, Auphan-Anezin N, Bebien M, Verthuy C, Vu Manh TP, Turner M, Dalod M, Schultze JL, Lawrence T

Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy.

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Cell metabolism, , 1932-7420, , 2019

PMID: 30930171


The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell-cell adhesion.
Fearnley GW, Young KA, Edgar JR, Antrobus R, Hay IM, Liang WC, Martinez-Martin N, Lin W, Deane JE, Sharpe HJ

Cell-cell communication in multicellular organisms depends on the dynamic and reversible phosphorylation of protein tyrosine residues. The receptor-linked protein tyrosine phosphatases (RPTPs) receive cues from the extracellular environment and are well placed to influence cell signaling. However, the direct events downstream of these receptors have been challenging to resolve. We report here that the homophilic receptor PTPRK is stabilized at cell-cell contacts in epithelial cells. By combining interaction studies, quantitative tyrosine phosphoproteomics, proximity labeling and dephosphorylation assays we identify high confidence PTPRK substrates. PTPRK directly and selectively dephosphorylates at least five substrates, including Afadin, PARD3 and δ-catenin family members, which are all important cell-cell adhesion regulators. In line with this, loss of PTPRK phosphatase activity leads to disrupted cell junctions and increased invasive characteristics. Thus, identifying PTPRK substrates provides insight into its downstream signaling and a potential molecular explanation for its proposed tumor suppressor function.

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eLife, 8, 2050-084X, , 2019

PMID: 30924770


Open Access

T cell stemness and dysfunction in tumors are triggered by a common mechanism.
Vodnala SK, Eil R, Kishton RJ, Sukumar M, Yamamoto TN, Ha NH, Lee PH, Shin M, Patel SJ, Yu Z, Palmer DC, Kruhlak MJ, Liu X, Locasale JW, Huang J, Roychoudhuri R, Finkel T, Klebanoff CA, Restifo NP

A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell-like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8 T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.

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Science (New York, N.Y.), 363, 1095-9203, , 2019

PMID: 30923193


The Aire family expands.
Liston A, Dooley J

T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of identifies ILC3-like cells in the lymph nodes with similar properties.

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The Journal of experimental medicine, , 1540-9538, , 2019

PMID: 30923044


Methods for measuring misfolded protein clearance in the budding yeast Saccharomyces cerevisiae.
Samant RS, Frydman J

Protein misfolding in the cell is linked to an array of diseases, including cancers, cardiovascular disease, type II diabetes, and numerous neurodegenerative disorders. Therefore, investigating cellular pathways by which misfolded proteins are trafficked and cleared ("protein quality control") is of both mechanistic and therapeutic importance. The clearance of most misfolded proteins involves the covalent attachment of one or more ubiquitin molecules; however, the precise fate of the ubiquitinated protein varies greatly, depending on the linkages present in the ubiquitin chain. Here, we discuss approaches for quantifying linkage-specific ubiquitination and clearance of misfolded proteins in the budding yeast Saccharomyces cerevisiae-a model organism used extensively for interrogation of protein quality control pathways, but which presents its own unique challenges for cell and molecular biology experiments. We present a fluorescence microscopy-based assay for monitoring the clearance of misfolded protein puncta, a cycloheximide-chase assay for calculating misfolded protein half-life, and two antibody-based methods for quantifying specific ubiquitin linkages on tagged misfolded proteins, including a 96-well plate-based ELISA. We hope these methods will be of use to the protein quality control, protein degradation, and ubiquitin biology communities.

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Methods in enzymology, 619, 1557-7988, 27-45, 2019

PMID: 30910025


Entosis Controls a Developmental Cell Clearance in C. elegans.
Lee Y, Hamann JC, Pellegrino M, Durgan J, Domart MC, Collinson LM, Haynes CM, Florey O, Overholtzer M

Metazoan cell death mechanisms are diverse and include numerous non-apoptotic programs. One program called entosis involves the invasion of live cells into their neighbors and is known to occur in cancers. Here, we identify a developmental function for entosis: to clear the male-specific linker cell in C. elegans. The linker cell leads migration to shape the gonad and is removed to facilitate fusion of the gonad to the cloaca. We find that the linker cell is cleared in a manner involving cell-cell adhesions and cell-autonomous control of uptake through linker cell actin. Linker cell entosis generates a lobe structure that is deposited at the site of gonad-to-cloaca fusion and is removed during mating. Inhibition of lobe scission inhibits linker cell death, demonstrating that the linker cell invades its host while alive. Our findings demonstrate a developmental function for entosis: to eliminate a migrating cell and facilitate gonad-to-cloaca fusion, which is required for fertility.

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Cell reports, 26, 2211-1247, 3212-3220.e4, 2019

PMID: 30893595


Open Access

ER platforms mediating autophagosome generation.
Ktistakis NT

The origin of the autophagosomal membrane started to be debated by scientists working in the field within one year of the modern definition of autophagy in 1963. There is now converging evidence from older and newer studies that the endoplasmic reticulum is involved in formation of autophagosomes. Thus, it is possible to trace from early morphological work - done without the benefit of molecular descriptions - to recent studies - dissecting how specific proteins nucleate autophagosome biogenesis - a long series of experimental findings that are beginning to answer the 55-year old question with some confidence. The view that has emerged is that specialised regions of the endoplasmic reticulum, in dynamic cross talk with most intracellular organelles via membrane contact sites, provide a platform for autophagosome biogenesis.

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Biochimica et biophysica acta. Molecular and cell biology of lipids, , 1879-2618, , 2019

PMID: 30890442


Relationship between pharmacokinetics and pharmacodynamic responses in healthy smokers informs a once daily dosing regimen for nemiralisib.
Begg M, Wilson R, Hamblin JN, Montembault M, Green J, Deans A, Amour A, Worsley S, Fantom K, Cui Y, Dear G, Ahmad S, Kielkowska A, Clark J, Boyce M, Cahn A, Hessel EM

Nemiralisib (GSK2269557) is a potent inhaled inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) which is being developed for the treatment of respiratory disorders including COPD (Chronic Obstructive Pulmonary Disease). Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n=56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1 mg to 6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% CI 11-34%) and 36% (90% CI 11-64%) following single dose or 14 days of treatment with nemiralisib respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ~3-4.5-fold (peak vs. trough) in plasma exposure following 14 days of nemiralisib treatment. BAL analysis at trough confirmed higher levels of drug in lung vs. plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). Comparison of drug levels in plasma and reductions in sputum PIP3 show a direct relationship between exposure and PIP3 reduction. In conclusion, these results demonstrate target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.

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The Journal of pharmacology and experimental therapeutics, , 1521-0103, , 2019

PMID: 30886125


Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes.
Van Nieuwenhove E, Lagou V, Van Eyck L, Dooley J, Bodenhofer U, Roca C, Vandebergh M, Goris A, Humblet-Baron S, Wouters C, Liston A

Juvenile idiopathic arthritis (JIA) is the most common class of childhood rheumatic diseases, with distinct disease subsets that may have diverging pathophysiological origins. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed.

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Annals of the rheumatic diseases, , 1468-2060, , 2019

PMID: 30862608


Signalling circuits that direct early B-cell development.
Petkau G, Turner M

In mammals, the B-cell lineage arises from pluripotent progenitors in the bone marrow. During their development, B-cells undergo lineage specification and commitment, followed by expansion and selection. These processes are mediated by regulated changes in gene expression programmes, rearrangements of immunoglobulin (Ig) genes, and well-timed rounds of proliferation and apoptosis. Many of these processes are initiated by environmental factors including cytokines, chemokines, and cell-cell contacts. Developing B-cells process these environmental cues into stage-specific functions via signalling pathways including the PI3K, MAPK, or JAK-STAT pathway. The cytokines FLT3-Ligand and c-Kit-Ligand are important for the early expansion of the B-cell precursors at different developmental stages and conditions. Interleukin 7 is essential for commitment to the B-cell lineage and for orchestrating the Ig recombination machinery. After rearrangement of the immunoglobulin heavy chain, proliferation and apoptosis, and thus selection, are mediated by the clonal pre-B-cell receptor, and, following light chain rearrangement, by the B-cell receptor.

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The Biochemical journal, 476, 1470-8728, 769-778, 2019

PMID: 30842310


Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation.
Kumar S, Gu Y, Abudu YP, Bruun JA, Jain A, Farzam F, Mudd M, Anonsen JH, Rusten TE, Kasof G, Ktistakis N, Lidke KA, Johansen T, Deretic V

Syntaxin 17 (Stx17) has been implicated in autophagosome-lysosome fusion. Here, we report that Stx17 functions in assembly of protein complexes during autophagy initiation. Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13FIP200 mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202. During autophagy induction, Stx17 transfers from the Golgi, where its steady-state pools localize, to the ATG13FIP200 mPAS. Stx17 was in complexes with ATG13 and FIP200, whereas its non-phosphorylatable mutant Stx17 was not. Stx17 or TBK1 knockouts blocked ATG13 and FIP200 puncta formation. Stx17 or TBK1 knockouts reduced the formation of ATG13 protein complexes with FIP200 and ULK1. Endogenous Stx17 colocalized with LC3B following induction of autophagy. Stx17 knockout diminished LC3 response and reduced sequestration of the prototypical bulk autophagy cargo lactate dehydrogenase. We conclude that Stx17 is a TBK1 substrate and that together they orchestrate assembly of mPAS.

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Developmental cell, , 1878-1551, , 2019

PMID: 30827897


Correction to: Comparison of whole-genome bisulfite sequencing library preparation strategies identifies sources of biases affecting DNA methylation data.
Olova N, Krueger F, Andrews S, Oxley D, Berrens RV, Branco MR, Reik W

Following publication of the original article [1], it was reported that the incorrect "Additional file 3" was published. The correct additional file is given below.

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Genome biology, 20, 1474-760X, 43, 2019

PMID: 30795792


Open Access