Quickscan science topics 2017

13 January 2018
#Glucocorticoid receptor #Second life as drug target #Cofactor profile fine-tuning
Glucocorticoids are steroid hormones with potent antiinflammatory and immune modulating effects. Recent key findings of Sofie Desmet and colleagues from the Jan Tavernier Lab (VIB-UGent Center for Medical Biotechnology) include, paradoxically, both pro- and anti-inflammatory roles of the glucocorticoid receptor (GR). Unraveling how GR ultimately shifts the balance to a net anti-inflammatory profile is a future challenge. The consensus is that GR deserves a second life as a drug target. Novel ligand combinations are one way to
approach this. Combining non-steroidal and steroidal ligands has shaped GR function towards a unique gene regulatory profile with stronger pro-inflammatory gene suppression and enhanced anti-inflammatory expression. The molecular basis hereof is a changed GR phosphorylation status concomitant with a unique cofactor recruitment profile.
Desmet et al., J. Clin. Invest. 2017
Desmet et al., Sci Rep. 2017

#Virotrap #SFINX #ProteinComplex
The analysis of protein complexes remains an important challenge, since virtually all methods require cell lysis and thus obliterate the cellular context. With Virotrap, the Sven Eyckerman Lab (VIB-UGent Center for Medical Biotechnology) has pioneered the trapping of protein complexes in virus-like particles, avoiding the homogenization step. This protocol paper now supports scientists who want to try the system on their favorite proteins. Analysis of the datasets is easy and intuitive with the straightforward filtering index (SFINX), a powerful contaminant removal tool (http://sfinx.ugent.be) that is included to complete the protocol.
Titeca & Van Quickelberghe et al., Nat Protoc 2017

#Pancreatic Cancer #autoimmunity #NOD
James Dooley and his colleagues of the Adrian Liston lab (VIB-KU Leuven Center for Brain & Disease research) studied the effect of immunological responses on pancreatic cancer in mice by backcrossing the Ela1-Tag transgenic model of pancreatic cancer onto the pancreatic autoimmune-susceptible NOD strain. Through longitudinal magnetic resonance imaging, they found that the NOD genetic background delayed the onset of pancreatic tumors and slowed their growth. These findings suggest that immune checkpoint blockade therapies that unleash latent autoimmunity could be useful to target pancreatic cancer.
Dooley et al., Oncotarget 2017

#Multi-domain protein #Acetylation #Intrinsically disordered protein
Protein acetylation modulates key functional protein interactions and gene expression in the cell. Accordingly, dysregulation of the underlying processes is involved in several diseases, such as Charcot-Marie-Tooth disease. One of the key proteins is the transcriptional coactivator CBP, which contains long intrinsically disordered regions (IDRs) thought to be passive “linkers” between its folded functional domains, such as the catalytic histone acetyl transferase (HAT) domain. Scientists of the Peter Tompa Lab (VIB-VUB Center for Structural Biology) showed that simultaneous interaction of the HAT domain and an ID region (ID3) with the substrate ZFP106 is required to target specific acetylation of ZFP106. They suggest that the regulatory phenomenon that arises might be a general mechanistic feature of the functioning of large multi-domainsignaling proteins. In a recent review, the Peter Tompa Lab also describes the ample evidence that the structural disorder of proteins (e.g. intrinsically disordered proteins/regions IDPs/IDRs) is prevalent in all organisms and plays important regulatory roles. However, the underlying evidence is mainly derived from in vitro biophysical studies. Here, the lab surveys direct and indirect in vivo evidence that structural disorder is in fact the physiological state of many proteins in the cell.
Contreras-Martos et al., Sci Rep. 2017
Pauwels et al., Cell Mol Life Sci. 2017

#Redox biology #Pathogens
Thienopyrimidine compounds such as TP053 are promising antitubercular drugs because they kill both replicating and non-replicating Mycobacterium tuberculosis. TP053 is a prodrug that must be activated by a bacterial endogenous enzyme whose function was previously unknown. Leonardo Rosado of the Joris Messens Lab (VIB-VUB Center for Structural Biology) characterized this enzyme and found that it is a mycoredoxin involved in the pathogen’s oxidative stress response. This mycoredoxin belongs to a new cluster of enzymes, paving the way for the correct classification of similar enzymes from other organisms.
Rosado et al., J Biol Chem 2017

#Cancer #Macrophages #Glutamine
The team of Massimiliano Mazzone (VIB-KU Leuven Center for Cancer Biology) showed that inhibiting the metabolic enzyme glutamine synthetase (GS) in pro-tumor (M2-like) macrophages reverts their polarization towards an HIF1alpha-mediated anti-tumor (M1-like) state, ultimately favoring cytotoxic T cell recruitment and blocking angiogenesis. As a consequence of a more pronounced immunostimulatory and anti-angiogenic
effect, genetic or pharmacologic inhibition of GS translates into the prevention of metastasis. These findings highlight the possibility of targeting this enzyme in the treatment of cancer.
Palmieri et al., Cell Reports 2017

#Angiogenesis #Endothelial cells #Glutamine
Endothelial cells (ECs) line blood vessels and are key players in the formation of new blood vessels (angiogenesis). Hongling Huang and Guy Eelen of the Peter Carmeliet Lab (VIB-KU Leuven Center for Cancer Biology) uncovered a crucial role for EC glutamine metabolism in angiogenesis. Glutaminedependent synthesis of asparagine allows ECs to maintain cellular homeostasis. Interestingly, blocking EC glutamine metabolism reduces pathological angiogenesis.
Huang H et al., EMBO J. 2017

#Orchid evolution #Genome duplication #Genomics
Scientists of the Yves Van de Peer Lab (VIB-UGent Center for Plant Systems Biology), together with researchers from China, Taiwan and Japan, have published the genome sequence of the orchid Apostasia shenzhenica in the journal Nature. Orchids represent about 10% of flowering plant species, are widely diverse in their morphology and lifestyle, and have successfully colonized almost every habitat on Earth. A. shenzhenica belongs to a small clade that diverged early and is a sister to the rest of the orchid family. Its genome revealed evidence of an ancient whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons with other orchids and flowering plants enabled the reconstruction of an ancestral orchid ‘gene toolkit’, shedding light on the genetic mechanisms underlying key orchid innovations, such as the labellum (a ‘lip’ on the flower that attracts insects) and the evolution of epiphytism (the ability to grow on another plant).
 Yves Van de Peer: “As computational biologists with an excellent reputation in evolutionary genomics and genome biology, we are increasingly asked to help turning new genome data into exciting biological stories. This is both a great honor and a true pleasure. The more because with every genome analyzed, we see Theodosius Dobzhansky’s famous adagium proven: ‘Nothing in Biology Makes Sense, Except in the Light of Evolution’.”
Zhang et al., Nature 2017

#LRRK2 #Protein dimerization #Parkinson’s disease
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The most frequent genetic cause of the illness are mutations in the gene coding for the protein LRRK2. Using bacterial homologues of LRRK2, the research team of Wim Versées of the Jan Steyaert Lab (VIB-VUB Center for Structural Biology) showed that this protein cycles between a monomeric and dimeric form. This conformational cycle is regulated by the GTPase domain of LRRK2. The observation that PD mutations affect this cycle might open new avenues for future PD drug discovery.
Deyaert, Wauters et al., Nat. Commun. 2017

#Asymmetric cell division #Spindle orientation #Physcomitrella patens
Cell division axis orientation is critical for differentiation and morphogenesis. In animals, centrosome-driven spindle orientation is key to orient divisions. However, in acentrosomal plants, the mechanism underlying spindle orientation is poorly understood. Ken Kosetsu and colleagues in the Daniel Van Damme Lab (VIB-UGent Center for Plant Systems Biology) and the Gohta Goshima Lab (Nagoya University, Japan) used asymmetrically dividing cells of the moss Physcomitrella patens and tobacco tissue culture cells for their research. They showed that de novo assembled prophase microtubule organizing centers are critical for spindle orientation assisting division plane orientation.
Kosetsu et al., PNAS 2017


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