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Simon Alberti, Dirk Dormann
Liquid-Liquid Phase Separation in Disease.
Annu. Rev. Genet., 53 171-194 (2019)
PubMed Source

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ability to develop effective disease treatments. To overcome this limitation, we need new concepts to describe and comprehend the complex mechanisms underlying human diseases. Condensate formation by phase separation emerges as a new principle to explain the organization of living cells. In this review, we present emerging evidence that aberrant forms of condensates are associated with many human diseases, including cancer, neurodegeneration, and infectious diseases. We examine disease mechanisms driven by aberrant condensates, and we point out opportunities for therapeutic interventions. We conclude that phase separation provides a useful new framework to understand and fight some of the most severe human diseases.

@article{Alberti7482,
author={Simon Alberti, Dirk Dormann},
title={Liquid-Liquid Phase Separation in Disease.},
journal ={Annual review of genetics},
volume={53},
pages={171--194},
year=2019
}

Nicole Prior, Patricia Inacio, Meritxell Huch
Liver organoids: from basic research to therapeutic applications.
Gut, 68(12) 2228-2237 (2019)
PubMed Source

Organoid cultures have emerged as an alternative in vitro system to recapitulate tissues in a dish. While mouse models and cell lines have furthered our understanding of liver biology and associated diseases, they suffer in replicating key aspects of human liver tissue, in particular its complex architecture and metabolic functions. Liver organoids have now been established for multiple species from induced pluripotent stem cells, embryonic stem cells, hepatoblasts and adult tissue-derived cells. These represent a promising addition to our toolbox to gain a deeper understanding of this complex organ. In this perspective we will review the advances in the liver organoid field, its limitations and potential for biomedical applications.

@article{Prior7527,
author={Nicole Prior, Patricia Inacio, Meritxell Huch},
title={Liver organoids: from basic research to therapeutic applications.},
journal ={Gut},
volume={68},
issue ={12},
pages={2228--2237},
year=2019
}

Anurag Priyam, Ben J Woodcroft, Vivek Rai, Ismail Moghul, Alekhya Munagala, Filip Ter, Hiten Chowdhary, Iwo Lukasz Pieniak, Lawrence J Maynard, Mark Anthony Gibbins, HongKee Moon, Austin Davis-Richardson, Mahmut Uludag, Nathan S Watson-Haigh, Rachel C Challis, Hiroyuki Nakamura, Emeline Favreau, Esteban A Gómez, Tomás Pluskal, Guy Leonard, Wolfgang Rumpf, Yannick Wurm
Sequenceserver: A Modern Graphical User Interface for Custom BLAST Databases.
Mol Biol Evol, 36(12) 2922-2924 (2019)
PubMed Source

Comparing newly obtained and previously known nucleotide and amino-acid sequences underpins modern biological research. BLAST is a well-established tool for such comparisons but is challenging to use on new data sets. We combined a user-centric design philosophy with sustainable software development approaches to create Sequenceserver, a tool for running BLAST and visually inspecting BLAST results for biological interpretation. Sequenceserver uses simple algorithms to prevent potential analysis errors and provides flexible text-based and visual outputs to support researcher productivity. Our software can be rapidly installed for use by individuals or on shared servers.

@article{Priyam7483,
author={Anurag Priyam, Ben J Woodcroft, Vivek Rai, Ismail Moghul, Alekhya Munagala, Filip Ter, Hiten Chowdhary, Iwo Lukasz Pieniak, Lawrence J Maynard, Mark Anthony Gibbins, HongKee Moon, Austin Davis-Richardson, Mahmut Uludag, Nathan S Watson-Haigh, Rachel C Challis, Hiroyuki Nakamura, Emeline Favreau, Esteban A Gómez, Tomás Pluskal, Guy Leonard, Wolfgang Rumpf, Yannick Wurm},
title={Sequenceserver: A Modern Graphical User Interface for Custom BLAST Databases.},
journal ={Molecular biology and evolution},
volume={36},
issue ={12},
pages={2922--2924},
year=2019
}

Antoine Graindorge, Inês Pinheiro, Anna Nawrocka, Allison C Mallory, Peter Tsvetkov, Noa Gil, Carlo Carolis, Frank Buchholz, Igor Ulitsky, Edith Heard, Mikko Taipale, Alena Shkumatava
In-cell identification and measurement of RNA-protein interactions.
Nat Commun, 10(1) Art. No. 5317 (2019)
PubMed Source

Regulatory RNAs exert their cellular functions through RNA-binding proteins (RBPs). Identifying RNA-protein interactions is therefore key for a molecular understanding of regulatory RNAs. To date, RNA-bound proteins have been identified primarily through RNA purification followed by mass spectrometry. Here, we develop incPRINT (in cell protein-RNA interaction), a high-throughput method to identify in-cell RNA-protein interactions revealed by quantifiable luminescence. Applying incPRINT to long noncoding RNAs (lncRNAs), we identify RBPs specifically interacting with the lncRNA Firre and three functionally distinct regions of the lncRNA Xist. incPRINT confirms previously known lncRNA-protein interactions and identifies additional interactions that had evaded detection with other approaches. Importantly, the majority of the incPRINT-defined interactions are specific to individual functional regions of the large Xist transcript. Thus, we present an RNA-centric method that enables reliable identification of RNA-region-specific RBPs and is applicable to any RNA of interest.

@article{Graindorge7563,
author={Antoine Graindorge, Inês Pinheiro, Anna Nawrocka, Allison C Mallory, Peter Tsvetkov, Noa Gil, Carlo Carolis, Frank Buchholz, Igor Ulitsky, Edith Heard, Mikko Taipale, Alena Shkumatava},
title={In-cell identification and measurement of RNA-protein interactions.},
journal ={Nature communications},
volume={10},
issue ={1},
pages={null--null},
year=2019
}

Melissa Bedard, Dilip Shrestha, David A Priestman, Yuting Wang, Falk Schneider, Juan D Matute, Shankar S Iyer, Uzi Gileadi, Gennaro Prota, Matheswaran Kandasamy, Natacha Veerapen, Gurdyal Besra, Marco Fritzsche, Sebastian Zeissig, Andrej Shevchenko, John C Christianson, Frances Platt, Christian Eggeling, Richard S Blumberg, Mariolina Salio, Vincenzo Cerundolo
Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells.
Proc Natl Acad Sci U.S.A., 116(47) 23671-23681 (2019)
PubMed Source

Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.

@article{Bedard7539,
author={Melissa Bedard, Dilip Shrestha, David A Priestman, Yuting Wang, Falk Schneider, Juan D Matute, Shankar S Iyer, Uzi Gileadi, Gennaro Prota, Matheswaran Kandasamy, Natacha Veerapen, Gurdyal Besra, Marco Fritzsche, Sebastian Zeissig, Andrej Shevchenko, John C Christianson, Frances Platt, Christian Eggeling, Richard S Blumberg, Mariolina Salio, Vincenzo Cerundolo},
title={Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={116},
issue ={47},
pages={23671--23681},
year=2019
}

Claire Basquin, Dmitry Ershov, Noémie Gaudin, Hanh Thi-Kim Vu, Bruno Louis, Jean-François Papon, Anne-Marie Orfila, Sarah Mansour, Jochen Rink, Juliette Azimzadeh
Emergence of a Bilaterally Symmetric Pattern from Chiral Components in the Planarian Epidermis.
Dev Cell, 51(4) 516-525 (2019)
PubMed Source

Most animals exhibit mirror-symmetric body plans, yet the molecular constituents from which they are formed are often chiral. In planarian flatworms, centrioles are arranged in a bilaterally symmetric pattern across the ventral epidermis. Here, we found that this pattern is generated by a network of centrioles with prominent chiral asymmetric properties. We identify centriole components required for establishing asymmetric connections between centrioles and balancing their effects to align centrioles along polarity fields. SMED-ODF2, SMED-VFL1, and SMED-VFL3 affect the assembly of centriole appendages that tether cytoskeletal connectors to position the centrioles. We further show that the medio-lateral polarization of centrioles relies on mechanisms that are partly distinct on the left and right sides of the planarian body. Our findings shed light on how bilaterally symmetrical patterns can emerge from chiral cellular organizations.

@article{Basquin7559,
author={Claire Basquin, Dmitry Ershov, Noémie Gaudin, Hanh Thi-Kim Vu, Bruno Louis, Jean-François Papon, Anne-Marie Orfila, Sarah Mansour, Jochen Rink, Juliette Azimzadeh},
title={Emergence of a Bilaterally Symmetric Pattern from Chiral Components in the Planarian Epidermis.},
journal ={Developmental cell},
volume={51},
issue ={4},
pages={516--525},
year=2019
}

Robert Haase, Loic Royer, Peter Steinbach, Deborah Schmidt, Alexandr Dibrov, Uwe Schmidt, Martin Weigert, Nicola Maghelli, Pavel Tomancak, Florian Jug, Eugene W Myers
CLIJ: GPU-accelerated image processing for everyone.
Nat Methods, Art. No. doi: 10.1038/s41592-019-0650-1 (2019)
PubMed Source

@article{Haase7557,
author={Robert Haase, Loic Royer, Peter Steinbach, Deborah Schmidt, Alexandr Dibrov, Uwe Schmidt, Martin Weigert, Nicola Maghelli, Pavel Tomancak, Florian Jug, Eugene W Myers},
title={CLIJ: GPU-accelerated image processing for everyone.},
journal ={Nature methods},
volume={},
pages={1--1},
year=2019
}

Hanh Thi-Kim Vu, Sarah Mansour, Michael Kücken, Corinna Blasse, Claire Basquin, Juliette Azimzadeh, Eugene W Myers, Lutz Brusch, Jochen Rink
Dynamic Polarization of the Multiciliated Planarian Epidermis between Body Plan Landmarks.
Dev Cell, 51(4) 526-542 (2019)
PubMed Source

Polarity is a universal design principle of biological systems that manifests at all organizational scales, yet its coordination across scales remains poorly understood. Here, we make use of the extreme anatomical plasticity of planarian flatworms to probe the interplay between global body plan polarity and local cell polarity. Our quantitative analysis of ciliary rootlet orientation in the epidermis reveals a dynamic polarity field with head and tail as independent determinants of anteroposterior (A/P) polarization and the body margin as determinant of mediolateral (M/L) polarization. Mathematical modeling rationalizes the global polarity field and its response to experimental manipulations as superposition of separate A/P and M/L fields, and we identify the core PCP and Ft/Ds pathways as their molecular mediators. Overall, our study establishes a framework for the alignment of cellular polarity vectors relative to planarian body plan landmarks and establishes the core PCP and Ft/Ds pathways as evolutionarily conserved 2D-polarization module.

@article{Vu7558,
author={Hanh Thi-Kim Vu, Sarah Mansour, Michael Kücken, Corinna Blasse, Claire Basquin, Juliette Azimzadeh, Eugene W Myers, Lutz Brusch, Jochen Rink},
title={Dynamic Polarization of the Multiciliated Planarian Epidermis between Body Plan Landmarks.},
journal ={Developmental cell},
volume={51},
issue ={4},
pages={526--542},
year=2019
}

Hauke Drechsler, Yong Xu, Veikko Geyer, Yixin Zhang, Stefan Diez
Multivalent electrostatic microtubule interactions of synthetic peptides are sufficient to mimic advanced MAP-like behavior.
Mol Biol Cell, 30(24) 2953-2968 (2019)
PubMed Source

Microtubule-associated proteins (MAPs) are a functionally highly diverse class of proteins that help to adjust the shape and function of the microtubule cytoskeleton in space and time. For this purpose, MAPs structurally support microtubules, modulate their dynamic instability, or regulate the activity of associated molecular motors. The microtubule-binding domains of MAPs are structurally divergent, but often depend on electrostatic interactions with the negatively charged surface of the microtubule. This suggests that the surface exposure of positive charges rather than a certain structural fold is sufficient for a protein to associate with microtubules. Consistently, positively charged artificial objects have been shown to associate with microtubules and to diffuse along their lattice. Natural MAPs, however, show a more sophisticated functionality beyond lattice-diffusion. Here, we asked whether basic electrostatic interactions are sufficient to also support advanced MAP functionality. To test this hypothesis, we studied simple positively charged peptide sequences for the occurrence of typical MAP-like behavior. We found that a multivalent peptide construct featuring four lysine-alanine heptarepeats (starPEG-(KA7)4)-but not its monovalent KA7-subunits-show advanced, biologically relevant MAP-like behavior: starPEG-(KA7)4 binds microtubules in the low nanomolar range, diffuses along their lattice with the ability to switch between intersecting microtubules, and tracks depolymerizing microtubule ends. Further, starPEG-(KA7)4 promotes microtubule nucleation and growth, mediates depolymerization coupled pulling at plus ends, and bundles microtubules without significantly interfering with other proteins on the microtubule lattice (as exemplified by the motor kinesin-1). Our results show that positive charges and multivalency are sufficient to mimic advanced MAP-like behavior.

@article{Drechsler7535,
author={Hauke Drechsler, Yong Xu, Veikko Geyer, Yixin Zhang, Stefan Diez},
title={Multivalent electrostatic microtubule interactions of synthetic peptides are sufficient to mimic advanced MAP-like behavior.},
journal ={Molecular biology of the cell},
volume={30},
issue ={24},
pages={2953--2968},
year=2019
}

Janelle Lauer, Sandra Segeletz, Alice Cezanne, Giambattista Guaitoli, Francesco Raimondi, Marc Gentzel, Vikram Alva, Michael Habeck, Yannis Kalaidzidis, Marius Ueffing, Andrei N Lupas, Christian Johannes Gloeckner, Marino Zerial
Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding.
Elife, 8 Art. No. e46302 (2019)
PubMed Source

Intracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be auto-inhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry. We generated a structural model of Rabex5, using chemical cross-linking mass spectrometry and integrative modeling techniques. By correlating structural changes with nucleotide exchange activity for each construct, we uncovered new auto-regulatory roles for the ubiquitin binding domains and the Linker connecting those domains to the catalytic core of Rabex5. We further provide evidence that enhanced dynamics in the catalytic core are linked to catalysis. Our results suggest a more complex auto-regulation mechanism than previously thought and imply that ubiquitin binding serves not only to position Rabex5 but to also control its Rab5 GEF activity through allosteric structural alterations.

@article{Lauer7553,
author={Janelle Lauer, Sandra Segeletz, Alice Cezanne, Giambattista Guaitoli, Francesco Raimondi, Marc Gentzel, Vikram Alva, Michael Habeck, Yannis Kalaidzidis, Marius Ueffing, Andrei N Lupas, Christian Johannes Gloeckner, Marino Zerial},
title={Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding.},
journal ={eLife},
volume={8},
pages={null--null},
year=2019
}