Immature truncated O-glycophenotype of cancer directly induces oncogenic features
Prakash Radhakrishnan, Sally Dabelsteen, Frey Brus Madsen, Chiara Francavilla, Katharina L. Kopp, Catharina Steentoft, Sergey Y. Vakhrushev, Jesper V. Olsen, Lars Hansen, Eric P. Bennett, Anders Woetmann, Guangliang Yin, Longyun Chen, Haiyan Song, Mads Bak, Ryan A. Hlady, Staci L. Peters, Rene Opavsky, Christenze Thode, Klaus Qvortrup, Katrine T.-B. G. Schjoldager, Henrik Clausen, Michael A. Hollingsworth, and Hans H. Wandall
Cancer cells characteristically express proteins with immature O-glycosylation, but how and why cancer cells express immature O-glycans has remained poorly understood. Here (pp. E4066–E4075), we report that one prevalent mechanism in pancreatic cancer is epigenetic silencing, rather than somatic mutations in a key chaperone, core 1 β3-Gal-T-specific molecular chaperone (COSMC), required for mature elongated O-glycosylation. We also demonstrate, with the use of well-defined cell systems generated by precise gene editing, that the aberrant O-glycophenotype by itself induces oncogenic features with enhanced growth and invasion. Our study suggests that the characteristic aberrant O-glycophenotype is critical for the development and behavior of cancer and further provides support for immunotherapeutic strategies that target aberrant O-glycans.
Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
Dana Westphal, Grant Dewson, Marie Menard, Paul Frederick, Sweta Iyer, Ray Bartolo, Leonie Gibson, Peter E. Czabotar, Brian J. Smith, Jerry M. Adams, and Ruth M. Kluck
To trigger cell death (apoptosis), two members of the B-cell lymphoma-2 protein family, Bak and Bax, change shape and convert from inert monomers into the oligomers that disrupt the outer mitochondrial membrane, but how they perturb the membrane is poorly understood. A longstanding model is that they rearrange and insert two central helices, α5 and α6, as a hairpin through the membrane. We show (pp. E4076–E4085), however, that the hairpin insertion model does not hold. Instead, these helices in the oligomers insert only shallowly in the membrane, in its plane. The results favor a model in which these and probably other helices of Bak and Bax crowd the outer leaflet of the membrane, producing membrane curvature that leads to its disruption.
Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development
Darshan Sapkota, Hemabindu Chintala, Fuguo Wu, Steven J. Fliesler, Zihua Hu, and Xiuqian Mu
We show (pp. E4086–E4095) that the onecut transcription factors, Onecut1 and Onecut2, redundantly regulate the formation of all four early-born retinal cell types, namely horizontal cells, ganglion cells, cones, and amacrine cells, and prevent precocious formation of the late retinal cell type, rods. Expression profiling suggests these two factors regulate a shared set of downstream genes to maintain competence for the early retinal cell types and to regulate generation of various subtypes of retinal ganglion cells. This study lays the foundation for further examination of how onecut factors regulate cell differentiation in the retina, as well as in the central nervous system in general.
Ecological and evolutionary significance of genomic GC content diversity in monocots
Petr Šmarda, Petr Bureš, Lucie Horová, Ilia J. Leitch, Ladislav Mucina, Ettore Pacini, Lubomír Tichý, Vít Grulich, and Olga Rotreklová
Our large-scale survey (pp. E4096–E4102) of genomic nucleotide composition across monocots has enabled the first rigorous testing, to our knowledge, of its biological significance in plants. We show that genomic DNA base composition (GC content) is significantly associated with genome size and holocentric chromosomal structure. GC content may also have deep ecological relevance, because changes in GC content may have played a significant role in the evolution of Earth’s biota, especially the rise of grass-dominated biomes during the mid-Tertiary. The discovery of several groups with very unusual GC contents highlights the need for in-depth analysis to uncover the full extent of genomic diversity. Furthermore, our stratified sampling method of distribution data and quantile regression-like logic of phylogenetic analyses may find wider applications in the analysis of spatially heterogeneous data.
Evolution of Drosophila sex comb length illustrates the inextricable interplay between selection and variation
Juan N. Malagón, Abha Ahuja, Gabilan Sivapatham, Julian Hung, Jiwon Lee, Sergio A. Muñoz-Gómez, Joel Atallah, Rama S. Singh, and Ellen Larsen
Not all possible biological shapes are actually seen in nature. Despite much experimental work, the developmental basis explaining the presence or absence of certain biological shapes remains poorly understood. We studied Drosophila melanogaster development using the sex comb, a group of modified bristles exhibiting spectacular morphological diversity among Drosophila species. We provide several lines of evidence (pp. E4103–E4109) suggesting that increasing D. melanogaster sex comb length produces a mechanical blockage, affecting comb shape and position. We infer that simple physical principles acting on tissues can influence the direction of evolution, and comparative studies of other fly species are consistent with this hypothesis. This work highlights the fundamental role of development for understanding biodiversity and evolution.
Hemolysis-induced lethality involves inflammasome activation by heme
Fabianno F. Dutra, Letícia S. Alves, Danielle Rodrigues, Patricia L. Fernandez, Rosane B. de Oliveira, Douglas T. Golenbock, Dario S. Zamboni, and Marcelo T. Bozza
Heme causes inflammation in sterile and infectious conditions, contributing to the pathogenesis of sickle cell disease, malaria, and sepsis, but the mechanisms by which heme operates are not completely understood. Here (pp. E4110–E4118) we show that heme induces IL-1β processing through the activation of the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages. Our results suggest that among NLRP3 activators, heme has common as well as unique requirements to trigger inflammasome activation. In vivo, hemolysis and heme cause inflammasome activation. Importantly, macrophages, inflammasome components, and IL-1R contribute to hemolysis-induced lethality. These results highlight the potential of understanding the molecular mechanisms by which heme is sensed by innate immune receptors as a way to identify new therapeutic strategies to treat the pathological consequences of hemolytic diseases.
B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS
Gabriel K. Pedersen, Monika Àdori, Sharesta Khoenkhoen, Pia Dosenovic, Bruce Beutler, and Gunilla B. Karlsson Hedestam
A subpopulation of antibody-secreting cells, B-1 cells, provides early protection against several types of pathogens. Both the development and function differ between B-1 cells and the better known B-2 cells, and exclusively B-1 cells are lacking in mice deficient for the nuclear inhibitory κB protein, IκBNS. B-1 cells mature similar to B-2 cells via a transitional stage. We demonstrate here (pp. E4119–E4126) the existence of a phenotypically distinct B-1 transitional B (TrB)-cell population in the neonatal spleen of wild-type mice. This TrB-1a–cell subset was lost in the absence of IκBNS, thus revealing a requirement for intact NF-κB signaling via IκBNS during this stage of the development of B-1 cells. Learning more about the development of B-1 cells may reveal new targets for therapeutic intervention.
Multiscale digital Arabidopsis predicts individual organ and whole-organism growth
Yin Hoon Chew, Bénédicte Wenden, Anna Flis, Virginie Mengin, Jasper Taylor, Christopher L. Davey, Christopher Tindal, Howard Thomas, Helen J. Ougham, Philippe de Reffye, Mark Stitt, Mathew Williams, Robert Muetzelfeldt, Karen J. Halliday, and Andrew J. Millar
Plants respond to environmental change by triggering biochemical and developmental networks across multiple scales. Multiscale models that link genetic input to the whole-plant scale and beyond might therefore improve biological understanding and yield prediction. We report (pp. E4127–E4136) a modular approach to build such models, validated by a framework model of Arabidopsis thaliana comprising four existing mathematical models. Our model brings together gene dynamics, carbon partitioning, organ growth, shoot architecture, and development in response to environmental signals. It predicted the biomass of each leaf in independent data, demonstrated flexible control of photosynthesis across photoperiods, and predicted the pleiotropic phenotype of a developmentally misregulated transgenic line. Systems biology, crop science, and ecology might thus be linked productively in a community-based approach to modeling.