PNAS PLUS

PNAS Plus Significance Statements PNAS PLUS

Recombinant silicateins as model biocatalysts in properties, occurring on attosecond timescales on up − organosiloxane chemistry (1 as = 10 18 s). The recent development of attosecond S. Yasin Tabatabaei Dakhili, Stephanie A. Caslin, Abayomi S. angle-resolved photoemission spectroscopy (atto- Faponle, Peter Quayle, Sam P. de Visser, and Lu Shin Wong ARPES) using high harmonic generation has opened – Organosiloxanes are components in a huge variety of up the possibility of probing electron electron interact- – consumer products and play a major role in the syn- ions in real time. In this paper, we distinguish electron thesis of fine chemicals. However, their synthetic electron screening and charge scattering in the time manipulation primarily relies on the use of chloro- domain in individual energy bands within a solid. silanes, which are energy-intensive to produce and These results open up new possibilities for probing – environmentally undesirable. Synthetic routes that fundamental electron electron interactions in a host of operate under ambient conditions and circumvent the materials including magnetic, superconducting, and – need for chlorinated feedstocks would therefore offer advanced quantum materials. (See pp. E5300 E5307.) a more sustainable route for producing this class of compounds. Here, a systematic survey is reported for Application of metabolic controls for the the silicatein enzyme, which is able to catalyze the maximization of lipid production in hydrolysis, condensation, and exchange of the sili- semicontinuous fermentation con–oxygen bond in a variety of organosiloxanes Jingyang Xu, Nian Liu, Kangjian Qiao, Sebastian Vogg, under environmentally benign conditions. These re- and Gregory Stephanopoulos sults suggest that silicatein is a promising candidate This work establishes a semicontinuous process for for development of selective and efficient biocatalysts efficient and complete upgrading of low-strength for organosiloxane chemistry. (See pp. E5285–E5291.) acetic acid into lipids. By implementing control strategies in response to the time-varying nature of Transitional–turbulent spots and turbulent– cell metabolism, we achieved and sustained lipid turbulent spots in boundary layers yields close to the theoretical maximum while main- taining high productivities. The control algorithm was Xiaohua Wu, Parviz Moin, James M. Wallace, Jinhie Skarda, Adrián Lozano-Durán, and Jean-Pierre Hickey designed to respond to readily available real-time measurements and basic principles, which is ideal for Uncovering the constitutive coherent structure in the in- industrial applications. Overall, our process scheme ner layer of the canonical turbulent boundary layer has can directly take in dilute nutrient streams that are remained a central fluid mechanics theme, because it difficult and costly to purify and is able to biologically tests our intellectual ability to understand even the sim- convert them into highly concentrated value-added plest external flow. We describe here how turbulent spots products. This design significantly reduces the energy are initiated in bypass boundary-layer transition and un- costs associated with processes using dilute feed- cover the ubiquity of concentrations of vortices in the fully stocks, which typically require initial concentration of turbulent region with characteristics remarkably like tran- the feed. (See pp. E5308–E5316.) sitional–turbulent spots. We present strong evidence that these concentrations of vortices are the constitutive co- Tetrahydrobiopterin regulates monoamine herent structure of the inner layer near the wall. This study neurotransmitter sulfonation contributes to the unification of understanding of phe- nomena occurring in boundary-layer late-stage transition Ian Cook, Ting Wang, and Thomas S. Leyh with near-wall turbulent boundary-layer structure and Human cytosolic sulfotransferases (SULTs) regulate dynamics in the developed flow. (See pp. E5292–E5299.) hundreds of signaling small molecules, yet little is known regarding their small-molecule regulation. Distinguishing attosecond electron–electron Members of the SULT1 family harbor a conserved scattering and screening in transition metals allosteric site that we hypothesize allows independent regulation of sulfonation in the 11 metabolic areas in Cong Chen, Zhensheng Tao, Adra Carr, Piotr Matyba, Tibor Szilvási, Sebastian Emmerich, Martin Piecuch, Mark Keller, Dmitriy which these isoforms operate. This hypothesis is val- Zusin, Steffen Eich, Markus Rollinger, Wenjing You, Stefan idated using SULT1A3, which sulfonates and inactivates Mathias, Uwe Thumm, Manos Mavrikakis, Martin Aeschlimann, monoamine neurotransmitters. During validation it was Peter M. Oppeneer, Henry Kapteyn, and Margaret Murnane discovered that tetrahydrobiopterin (THB), an essential Electron–electron interactions are among the fastest cofactor in monoamine neurotransmitter biosynthesis,

processes in materials that determine their fascinating allosterically inhibits SULT1A3 with high affinity (Ki,23nM)

www.pnas.org/cgi/doi/10.1073/pnas.ss11427 PNAS | July 3, 2017 | vol. 114 | no. 27 | 6891–6894 Downloaded by guest on September 24, 2021 and isozyme selectivity. Monoamine neurotransmitter metabolism C2B–SNAP25 and Rph3A C2B–PIP2 complexes, we revealed a shapes human behavior and social interactions and is a thera- membrane-binding mode in which the Rph3A-C2 domains operate 2+ peutic target. These findings provide a paradigm for regulating in cooperation with PIP2/Ca and SNAP25, adopting a confor- sulfonation and a target for controlling neurotransmitter activity. mation able to promote membrane bending, suggesting a model (See pp. E5317–E5324.) to explain how Rph3A regulates various steps of the vesicle fusion process. (See pp. E5343–E5351.) Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and Uncovering BRD4 hyperphosphorylation associated with acyl-ACP–ISD11 interactions cellular transformation in NUT midline carcinoma Seth A. Cory, Jonathan G. Van Vranken, Edward J. Brignole, Shachin Patra, Ranran Wang, Xing-Jun Cao, Katarzyna Kulej, Wei Liu, Tongcui Ma, Margo Dennis R. Winge, Catherine L. Drennan, Jared Rutter, MacDonald, Cheng-Ming Chiang, Benjamin A. Garcia, and Jianxin You and David P. Barondeau BRD4 plays a vital role in cellular growth control. Because BRD4 is Prokaryotic and eukaryotic organisms use analogous pathways dysregulated in a wide range of aggressive malignancies, it is to synthesize protein cofactors called iron–sulfur clusters. An being increasingly implicated as a major driver of oncogenic unexplained difference between pathways is the functional re- growth and a novel target for cancer therapy. However, how quirements of the respective cysteine desulfurases. In eukary- BRD4 is regulated to maintain its normal function in healthy cells otes, the cysteine desulfurase NFS1 requires additional accessory and how alteration of this process leads to cancer remain poorly subunits for function. The lack of structural information has lim- understood. We discovered that BRD4 is hyperphosphorylated in ited mechanistic insight into the role of these accessory proteins cancers and that this hyperphosphorylation may be a general in mitochondrial Fe–S cluster biosynthesis. Here we determined mechanism to support its oncogenic activities. Our study shows crystallographic and electron microscopic structures of the how dysregulation of BRD4 function could lead to tumorigene- NFS1–ISD11–ACP subcomplex. These results reveal an unex- sis. Our discovery also provides the rationale for investigating pected cysteine desulfurase architecture that reconciles mecha- how cellular signaling pathways modulate BRD4 phosphorylation nistic differences between the prokaryotic and eukaryotic systems, to control its function during cancer development. (See pp. reveals the basis of control of iron–sulfur cluster assembly through E5352–E5361.) fatty acid synthesis, and serves as a structural foundation for in- vestigating human diseases related to iron–sulfur cluster assembly. Bacteria-mediated hypoxia functions as a signal for (See pp. E5325–E5334.) mosquito development Kerri L. Coon, Luca Valzania, David A. McKinney, Kevin J. Vogel, Mark R. Role of the CBP catalytic core in intramolecular Brown, and Michael R. Strand SUMOylation and control of histone H3 acetylation Mosquitoes are important insects because several species transmit Sangho Park, Robyn L. Stanfield, Maria A. Martinez-Yamout, H. Jane pathogens as adults that cause disease in humans and other verte- Dyson, Ian A. Wilson, and Peter E. Wright brates. One approach for control is preventing immature mosquitoes CREB-binding protein (CBP) and its paralog p300 play a vital role from developing into adults. Immature-stage mosquitoes require gut in regulating gene transcription. Through the enzymatic activ- bacteria to develop, but the mechanisms underlying this de- ity of their histone acetyltransferase (HAT) domain, CBP and pendence are unknown. Here, we identify cytochrome bd oxidase as p300 control the accessibility of genes in chromatin and activate a bacterial product involved in mosquito development. We also transcription. They also function as transcriptional repressors show that bacteria-mediated reduction of oxygen levels in the di- following SUMOylation of the cell cycle regulatory domain 1 gestive tract of larvae serves as a signal for molting. These findings (CRD1) located N-terminal to the catalytic core. We present provide the first evidence that aerobic respiration by bacteria plays structural and biochemical results showing that the CBP bromo- an essential role in mosquito development. This information can also domain, CH2, and ZZ domains, which flank the acetyltransferase potentially be used to develop tools for disabling the growth of larval domain, regulate acetyltransferase activity and also promote mosquitoes into adults. (See pp. E5362–E5369.) SUMOylation of the adjacent CRD1 cell cycle regulatory domain. This study provides insights into the function of the catalytic core TCTE1 is a conserved component of the dynein regulatory and the role of adjacent domains and a disordered regulatory complex and is required for motility and metabolism in loop in mediating CBP/p300 activity. (See pp. E5335–E5342.) mouse spermatozoa – Julio M. Castaneda, Rong Hua, Haruhiko Miyata, Asami Oji, Yueshuai Guo, Structural characterization of the Rabphilin-3A Yiwei Cheng, Tao Zhou, Xuejiang Guo, Yiqiang Cui, Bin Shen, Zibin Wang, SNAP25 interaction Zhibin Hu, Zuomin Zhou, Jiahao Sha, Renata Prunskaite-Hyyrylainen, Zhifeng Yu, Ramiro Ramirez-Solis, Masahito Ikawa, Martin M. Matzuk, Cristina Ferrer-Orta, María Dolores Pérez-Sánchez, Teresa Coronado-Parra, and Mingxi Liu Cristina Silva, David López-Martínez, Jesús Baltanás-Copado, Juan Carmelo Gómez-Fernández, Senena Corbalán-García, Infertility is a global problem that afflicts 15% of couples, and in 50% and Núria Verdaguer of cases, the attributing factor is linked to men. Among these infertile Membrane fusion is essential in multiple cell processes, including men, 18% specifically exhibit decreased motility of sperm (astheno- neuronal communication. Numerous proteins are recruited to the zoospermia). Sperm motility is dependent on the formation and presynaptic space to execute a highly controlled process, resulting functioning of the flagellum, a modified cilium used for locomotion. in the liberation of neurotransmitters. Many of these proteins share Cilia are present in almost every cell of vertebrates and are essential C2 domains as common structural motifs, regulated by their ability for proper organ functioning. Defects in cilia formation lead to severe + to bind Ca2 , phospholipids, and other proteins, endowing them syndromic diseases, termed ciliopathies, affecting numerous tissues with properties to fine-tune a wide variety of vesicle release (e.g., polycystic kidney disease), wherein male infertility is often modes. Here, by solving the structures of Rabphilin-3A (Rph3A) comorbid. Advances in mouse genetics implicate several genes

6892 | www.pnas.org/cgi/doi/10.1073/pnas.ss11427 Downloaded by guest on September 24, 2021 responsible for ciliopathies observed in humans. Here, we identify a sperm. Here, we investigated the molecular and functional speci- nonsyndromic flagellum protein, TCTE1, that is required for sperm ficity of the butterfly spermatophore, a structurally complex ejacu- motility in mice. (See pp. E5370–E5378.) late. We discovered that its two distinct parts originate from separate regions of the male reproductive tract, are transferred se- Reconstruction and evolutionary history of quentially during mating, and seem to be the result of a complex eutherian chromosomes evolutionary history. We also highlight a large and previously un- recognized female contribution to the spermatophore, which calls Jaebum Kim, Marta Farré, Loretta Auvil, Boris Capitanu, Denis M. Larkin, Jian Ma, and Harris A. Lewin into question traditional characterizations of females as passive re- cipients of these male ejaculates. (See pp. E5406–E5413.) Determining the order and orientation of conserved chromosome segments in the genomes of extant mammals is important for A null model for microbial diversification understanding speciation events, and the lineage-specific adap- tations that have occurred during ∼200 My of mammalian evolution. Timothy J. Straub and Olga Zhaxybayeva In this paper, we describe the computational reconstruction of When evolutionary histories of closely related microorganisms are chromosome organization for seven ancestral genomes leading to reconstructed, the lineages often cluster into visibly recognizable human, including the ancestor of all placental mammals. The evo- groups. However, we do not know if these clusters represent lutionary history of chromosome rearrangements that occurred from fundamental units of bacterial diversity, such as “species,” nor do the time of the eutherian ancestor until the human lineage is we know the nature of evolutionary and ecological forces that are revealed in detail. Our results provide an evolutionary basis for responsible for cluster formation. Addressing these questions is comparison of genome organization of all eutherians, and for re- crucial, both for describing biodiversity and for rapid and un- vealing the genomic origins of lineage-specific adaptations. (See pp. ambiguous identification of microorganisms, including patho- E5379–E5388.) gens. Multiple competing scenarios of ecological diversification have been previously proposed. Here we show that simple cell Stem caecilian from the Triassic of Colorado sheds light on death and division over time could also explain the observed the origins of Lissamphibia clustering. We argue that testing for the signatures of such “neutral” patterns should be considered a null hypothesis in any Jason D. Pardo, Bryan J. Small, and Adam K. Huttenlocker microbial classification analysis. (See pp. E5414–E5423.) Research into modern amphibian origins is increasingly focusing on the limbless caecilians, a poorly studied group whose pre-Cenozoic Evolutionary radiation of lanthipeptides in fossils are limited to two species. We describe tiny fossils from the marine cyanobacteria Triassic of Colorado with a mixture of traits found in caecilians and Andres Cubillos-Ruiz, Jessie W. Berta-Thompson, Jamie W. Becker, – extinct Permian Triassic temnospondyls: Stereospondyli. Computed Wilfred A. van der Donk, and Sallie W. Chisholm 3D tomography shows how skull bones organized around internal Lanthipeptides are a large family of microbial natural products of structures, and we suggest how these may have become fused or ribosomal origin. Prochlorosins are a group of unusually diverse simplified in caecilians. The fossils’ association with burrows highlights lanthipeptides found in strains of the marine cyanobacteria Pro- ecological diversity of Triassic amphibians as well as when and how chlorococcus and Synechococcus—the most abundant photo- burrowing evolved in the stereospondyl ancestors of caecilians. Our synthetic microorganisms on Earth. By analyzing the prochlorosin narrative for research on amphibian origins highlights the importance biosynthesis genes from cultured strains and wild cyanobacteria, of stereospondyls, the most numerous and anatomically diverse we show that the global collective of these microorganisms has amphibian group of the Triassic. (See pp. E5389–E5395.) evolved thousands of structurally distinct lanthipeptides via a process of evolutionary radiation favoring the sustained emer- The Red Queen and King in finite populations gence of new structures over refinement of an existing one. The Carl Veller, Laura K. Hayward, Christian Hilbe, and Martin A. Nowak evolutionary history of prochlorosins suggests a fundamentally When two populations interact, when does it pay to evolve different structure-to-function relationship compared with other rapidly, and can it ever be an advantage to evolve slowly? We lanthipeptides and opens the question of how structural di- address these questions using evolutionary game theory. In an- versification contributes to their function and mode of action in tagonistic interactions (e.g., host–parasite), we find that faster the marine environment. (See pp. E5424–E5433.) evolution by any means is beneficial—the “Red Queen” effect. In certain mutualisms, slower evolution is favored in the long run. Multiple layers of heterogeneity and subset diversity in This “Red King” effect is driven by differences in how efficiently human MAIT cell responses to distinct microorganisms natural selection acts in the two populations, rather than by dif- and to innate cytokines ferences in their generation times or mutation rates. Our results Joana Dias, Edwin Leeansyah, and Johan K. Sandberg clarify the role of evolutionary rate in symbiont evolution. (See pp. Mucosa-associated invariant T (MAIT) cells are a large subset of E5396–E5405.) unconventional T cells in humans, recognizing microbial riboflavin metabolites presented by the monomorphic MR1 molecule. The ex- Structural complexity and molecular heterogeneity of a traordinary level of conservation of MR1 and the limited diversity butterfly ejaculate reflect a complex history of selection of riboflavin-derived antigens have suggested that MAIT cells are Camille Meslin, Tamara S. Cherwin, Melissa S. Plakke, Brandon S. Small, homogeneous, and their functional specialization has not been Breanna J. Goetz, Nathan I. Morehouse, and Nathan L. Clark thoroughly investigated. Here, we show that MAIT cell responses Male ejaculates exhibit remarkable diversity, including variation in against two distinct riboflavin biosynthesis-competent microorgan- their spatial and temporal molecular composition. This complexity isms display microbe-specific response patterns with multiple layers suggests that ejaculates provide functions far beyond the delivery of of heterogeneity. Furthermore, a set of natural killer cell-associated

PNAS | July 3, 2017 | vol. 114 | no. 27 | 6893 Downloaded by guest on September 24, 2021 receptors define a subset with enhanced capacity to respond to mediated axon regeneration and opening novel treatment innate cytokine stimulus. Thus, MAIT cells harbor multiple layers of possibilities for CNS repair. (See pp. E5454–E5463.) functional heterogeneity and can adapt their antimicrobial responses – to the type of microbial stimuli. (See pp. E5434 E5443.) Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need Virus-induced inflammasome activation is suppressed by Anne Vassalli and Paul Franken prostaglandin D2/DP1 signaling Rahul Vijay, Anthony R. Fehr, Ann M. Janowski, Jeremiah Athmer, Dorthea L. As in narcolepsy patients, overall time spent awake and asleep is Wheeler, Matthew Grunewald, Ramakrishna Sompallae, Samarchith P. normal in mice lacking the wake-enhancing neuromodulator Kurup, David K. Meyerholz, Fayyaz S. Sutterwala, Shuh Narumiya, hypocretin/orexin. We discovered, however, that these mice, in and Stanley Perlman baseline conditions, are impaired in maintaining theta-dominated Inflammatory responses to viral infections must be optimized to wakefulness (TDW), a waking substate characteristic of goal-driven, clear the pathogen without tissue damage. Inflammasomes com- explorative behaviors and associated with heightened θ/fast-γ ac- prise an important component of the innate immune response. tivity. We demonstrate that TDW instability causes profound Inflammasome activity must be carefully controlled to prevent a blunting of EEG δ activity in subsequent slow-wave sleep, a measure hyperinflammatory response, especially in brain infections. Here we gauging homeostatic sleep need. In contrast, manually enforced identify a host factor, PYDC3, that is dependent upon prostaglandin waking induced unimpaired TDW expression and normal δ activity

D2 (PGD2) and IFN-I signaling and is required to modulate inflam- in recovery sleep. This suggests that TDW, not overall waking, masome activation. After infection, inflammasome activation and drives sleep need, a hypothesis we verified by modeling the ho- expression of a downstream proinflammatory cytokine, IL-1β,were meostatic process. We propose that Hcrt is critical for spontaneous

increased in mice deficient in PGD2 signaling, decreasing survival. waking but that enforced waking relies on other neuromodulators, Excess mortality was reversed by IL-1β receptor blockade. These such as norepinephrine. (See pp. E5464–E5473.) results define a consequence of prostaglandin signaling and shed light on prostaglandin–inflammasome interactions, which mod- Sex-specific early survival drives adult sex ratio bias in ulate excessive inflammation andtissuedamageinthevirus- snowy plovers and impacts mating system and infected brain. (See pp. E5444–E5453.) population growth Luke J. Eberhart-Phillips, Clemens Küpper, Tom E. X. Miller, Medardo Boosting CNS axon regeneration by harnessing Cruz-López, Kathryn H. Maher, Natalie dos Remedios, Martin A. Stoffel, antagonistic effects of GSK3 activity Joseph I. Hoffman, Oliver Krüger, and Tamás Székely Marco Leibinger, Anastasia Andreadaki, Renate Golla, Evgeny Levin, Sex biases are widespread in nature and represent a fundamental Alexander M. Hilla, Heike Diekmann, and Dietmar Fischer component of sexual selection and population biology—but at The role of GSK3 in axon regeneration is controversial. Whereas which point in life history do these biases emerge? We report a increased GSK3 activity accelerates peripheral nerve regeneration, it detailed individual-based demographic analysis of an intensively shows the opposite effect in the CNS. Moreover, KO/knockdown of studied wild bird population to evaluate origins of sex biases GSK3β in growth-stimulated retinal ganglion cells (RGCs) was dis- and their consequences on mating strategies and population inhibitory and potentiated optic nerve regeneration. This dichotomy dynamics. We document a strongly male-biased adult sex ratio, was the result of a GSK3-dependent and CNS-specific inhibition of which is consistent with behavioral observations of female-biased axonal CRMP2, which compromised RGCs’ ability for axon growth. polygamy. Notably, sexbiased juvenile rather than adult survival As GSK3 inhibition, neuronal expression of constitutively ac- contributed most to the adult sex ratio. Sex biases also tive CRMP2 (CRMP2T/A) potentiated optic nerve regeneration strongly influenced population viability, which was signifi- and, strikingly, unmasked an axon growth-promoting effect cantly overestimated when sex ratio and mating system were of active GSK3 as in peripheral nerves. CRMP2T/A expression ignored. Our study, therefore, has implications for both sex- and GSK3 activation additively enabled extensive optic nerve ual selection theory and biodiversity conservation. (See pp. regeneration, thereby reconciling conflicting data in GSK3- E5474–E5481.)

6894 | www.pnas.org/cgi/doi/10.1073/pnas.ss11427 Downloaded by guest on September 24, 2021