Effect of material flexibility on the thermodynamics and kinetics of hydrophobically induced evaporation of water
Y. Elia Altabet, Amir Haji-Akbari (
), and Pablo G. Debenedetti
The evaporation of water in hydrophobic confinement is important for the formation and function of both natural and synthetic hydrophobic self-assemblies. Using advanced computational techniques, we find that the thermodynamic and kinetic stability of water in hydrophobic confinement is extremely sensitive to the flexibility of the confining material. In the context of engineered systems, this work suggests that the mechanical properties of the building blocks in a self-assembled system are a crucial design consideration. With respect to biophysical phenomena, it suggests that small changes in flexibility can induce switch-like responses such as the opening and closing of membrane channels and the conversion between active and inactive states in receptors, both of which are common drug targets. (See pp. E2548–E2555.)
Electron transfer between anatase TiO2 and an O2 molecule directly observed by atomic force microscopy
Martin Setvin, Jan Hulva, Gareth S. Parkinson, Michael Schmid, and Ulrike Diebold
Molecular oxygen is an inert species, unable to enter chemical reactions. Activation occurs through the acceptance of an extra electron; this catalytic step plays a major role in applications such as heterogeneous catalysis and fuel cells. It is also used by all living organisms. We show that the two different charge states of O2 can be easily distinguished by atomic force microscopy (AFM). We directly injected or removed electrons into/from the O2 molecule by the AFM tip, switching the O2 reactivity. These results open new possibilities for studying catalytic and photocatalytic processes. (See pp. E2556–E2562.)
Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ
Chyuan-Chuan Wu, Thomas J. Baiga, Michael Downes, James J. La Clair, Annette R. Atkins, Stephane B. Richard, Weiwei Fan, Theresa A. Stockley-Noel, Marianne E. Bowman, Joseph P. Noel, and Ronald M. Evans
Clinical treatments for metabolic diseases rely on agents with high selectivity to specific targets often within a class of structurally and functionally related proteins. In this paper, we uncover physical and chemical features governing selective small-molecule binding to peroxisome proliferator-activated receptor (PPAR) δ concomitant with distinct conformational changes in the receptor, key to therapeutic modulation of lipid catabolism, transport, and storage. These studies reveal the subtle interplay between ligand configuration and chemistry coupled to modulation of PPARδ structural dynamics. This set of structure–activity relationships (SARs) guide synthetic ligand designs necessary to refine therapeutic leads for temporally and spatially regulating PPARδ during the course of metabolic disease onset and progression. (See pp. E2563–E2570.)
Biological regulation of atmospheric chemistry en route to planetary oxygenation
Gareth Izon, Aubrey L. Zerkle, Kenneth H. Williford, James Farquhar, Simon W. Poulton, and Mark W. Claire
It has been proposed that enhanced methane fluxes to Earth’s early atmosphere could have altered atmospheric chemistry, initiating a hydrocarbon-rich haze reminiscent of Saturn’s moon Titan. The occurrence, cause, and significance of haze development, however, remain unknown. Here, we test and refine the “haze hypothesis” by combining an ultra-high-resolution sulfur- and carbon-isotope dataset with photochemical simulations to reveal the structure and timing of haze development. These data suggest that haze persisted for ∼1 million years, requiring a sustained biological driver. We propose that enhanced atmospheric CH4, implied by the presence of haze, could have had a significant impact on the escape of hydrogen from the atmosphere, effectively contributing to the terminal oxidation of Earth’s surficial environments ∼2.4 billion years ago. (See pp. E2571–E2579.)
Optimal run-and-tumble–based transportation of a Janus particle with active steering
Tomoyuki Mano, Jean-Baptiste Delfau, Junichiro Iwasawa, and Masaki Sano
Commanding the swimming of micrometric objects subjected to thermal agitation is always challenging for both artificial and living systems. Now, artificial swimmers can be designed with self-propelling force that can be tuned at will. However, orienting such small particles to an arbitrary direction requires counterbalancing the random rotational diffusion. Here, we introduce a simple concept to reorient artificial swimmers, granting them a motion similar to the run-andtumbling behavior of Escherichia coli. We show it using Janus particles with asymmetric surface coating and moving under an ac electric field. Moreover, we determine the optimal strategy and compare it with biological swimmers. Our results encourage additional investigation into dynamical behavior of colloidal particles as well as application to microscopic devices. (See pp. E2580–E2589.)
Cross-cousin marriage among the Yanomamö shows evidence of parent–offspring conflict and mate competition between brothers
Napoleon A. Chagnon, Robert F. Lynch, Mary K. Shenk, Raymond Hames, and Mark V. Flinn
Cross-cousin marriage (i.e., marriage with the offspring of a parent's opposite-sex sibling) is the most common preferred marriage arrangement across cultures. Despite intense investigation, the origin and adaptive function of this marriage prescription have not been resolved. An analysis of the fitness consequences of marriages in the Yanomamö—a tribal society in the Amazon—shows that parents and brothers achieve higher fitness outcomes when their respective children and sisters marry more closely related individuals. Meanwhile, the spouses and offspring produced by these unions have lower fitness. These findings suggest that cross-cousin marriage prescriptions and taboos against marrying parallel cousins owe their origin to parent–offspring conflict through parental control of marriage and competition between same-sex siblings. (See pp. E2590–E2597.)
Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity
Matthew W. Klinker, Ross A. Marklein, Jessica L. Lo Surdo, Cheng-Hong Wei, and Steven R. Bauer
Substantial evidence exists demonstrating the immunosuppressive function of mesenchymal stromal cells (MSCs), but inconsistent clinical results suggest that better understanding of MSC-mediated immunosuppression and identification of features predictive of immunosuppressive capacity would advance MSC-based therapeutics. In this work, we present a robust analytical approach to quantify the immunosuppressive capacity of MSCs by integrating high-dimensional flow cytometry data from multiple experimental conditions into a single measure of immunosuppressive capacity. Additionally, we identified morphological features of MSCs that predicted immunosuppressive capacity, as well as the magnitude of IFN-γ–mediated immunosuppression enhancement. These improved methods of MSC characterization could be used to identify MSC preparations with desired immunosuppressive capacity, as well as screen for pretreatments that enhance their immunosuppressive function. (See pp. E2598–E2607.)
Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism
Sahil Gulati, Beata Jastrzebska, Surajit Banerjee, Ángel L. Placeres, Przemyslaw Miszta, Songqi Gao, Karl Gunderson, Gregory P. Tochtrop, Sławomir Filipek, Kota Katayama, Philip D. Kiser, Muneto Mogi, Phoebe L. Stewart, and Krzysztof Palczewski
Vertebrate rhodopsin (Rh) has been a model system for many G protein-coupled receptors for over a decade. However, due to its thus-far limited repertoire of active ligands, its use in assisting the development of new therapeutic modalities and drugs has been limited. This study elucidates a photocyclic G protein activation by Rh bound with a six-carbon ring retinal (Rh6mr), and thus broadens the diversity of such Rh signaling modulators. Rh6mr does not release its chromophore after light activation, but instead the resulting photoproduct is thermally reisomerized back to its inactive state, abrogating the necessity for a complex retinoid cycle to renew its chromophore. This photocyclic behavior of Rh6mr opens up several avenues for using optogenetic tools based on vertebrate Rhs. (See pp. E2608–E2615.)
Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum
Takuya Kitamura, Naoya Seki, and Akio Kihara
Although the synthetic pathway of phytosphingosine is already known, its degradation pathway has remained unclear. In the present study, we reveal the entire phytosphingosine degradation pathway, where fatty acid α-oxidation is involved. We show that the Sjögren–Larsson syndrome-causative gene ALDH3A2 and HACL2 (2-hydroxyacyl-CoA lyase 2) are involved in the fatty acid α-oxidation reactions as an aldehyde dehydrogenase and a 2-hydroxy acyl-CoA lyase, respectively. Our findings are important for understanding the molecular mechanism of phytosphingosine/sphingolipid homeostasis. HACL2 is localized in the endoplasmic reticulum, indicating that fatty acid α-oxidation occurs in the endoplasmic reticulum in mammals, in addition to the α-oxidation already known to occur in peroxisomes. (See pp. E2616–E2623.)
Structure-guided SCHEMA recombination generates diverse chimeric channelrhodopsins
Claire N. Bedbrook, Austin J. Rice, Kevin K. Yang, Xiaozhe Ding, Siyuan Chen, Emily M. LeProust, Viviana Gradinaru, and Frances H. Arnold
Critical for regulating cell function, integral membrane proteins (MPs) are key engineering targets. MP engineering is limited because these proteins are difficult to express with proper plasma membrane localization in heterologous systems. We investigate the expression, localization, and light-induced behavior of the light-gated MP channel, channelrhodopsin (ChR), because of its utility in studying neuronal circuitry. We used structure-guided SCHEMA recombination to generate libraries of chimeric ChRs that are diverse in sequence yet still capable of efficient expression, localization, and useful light-induced functionality. The conservative nature of recombination generates unique protein sequences that tend to fold and function. Recombination is also innovative: chimeric ChRs can outperform their parents or even exhibit properties not known in natural ChRs. (See pp. E2624–E2633.)
Multisite aggregation of p53 and implications for drug rescue
GuoZhen Wang and Alan R. Fersht
Destabilized mutants of the tumor suppressor p53 are inactivated by self-aggregation in a substantial number of tumors and may also coaggregate with and inactivate WT p53 and family members. We found in vitro that self-aggregation proceeded via a network of multiple aggregation-prone sites in p53, and inhibition of an individual site did not inhibit aggregation. Nevertheless, peptides designed to be complementary to various aggregation sequences and inhibit their polymerization can specifically kill cancer cells and be potential anticancer drugs. We found that those peptides can also function by p53-independent routes in cancer cell cultures, implying further therapeutic targets. (See pp. E2634–E2643.)
Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity
Prakash Kulkarni, Mohit Kumar Jolly, Dongya Jia, Steven M. Mooney, Ajay Bhargava, Luciane T. Kagohara, Yihong Chen, Pengyu Hao, Yanan He, Robert W. Veltri, Alexander Grishaev, Keith Weninger, Herbert Levine, and John Orban
The onset of androgen resistance is a major impediment in treating prostate cancer (PCa). However, the underlying molecular mechanisms are not fully understood. Here, we integrate multiple biophysical approaches that report conformational preferences of the intrinsically disordered protein (IDP) Prostate-Associated Gene 4 (PAGE4) with human cancer biology and nonlinear dynamics. Based on our biophysical, biochemical, and cellular data, a mathematical model is presented that suggests a mechanism by which phosphorylation-induced conformational changes in PAGE4 can switch from an androgen-dependent phenotype to an androgen-independent phenotype in PCa cells. The study underscores how IDPs that engage in multiple “promiscuous” interactions due to their conformational dynamics when overexpressed or aberrantly expressed can stochastically orchestrate phenotypic heterogeneity in PCa. (See pp. E2644–E2653.)
Bacterial proteostasis balances energy and chaperone utilization efficiently
Mantu Santra, Daniel W. Farrell, and Ken A. Dill
A cell's proteins must be properly folded. Therefore, cells have chaperones that help other proteins, their clients, fold and not aggregate. The machinery is like a hospital: it assesses the “sickness” of the patient (finds improperly folded proteins), sends the patient to the right doctor (sorts the protein to the right chaperone), and cures the disease (folds or disaggregates the protein). How are sick proteins recognized and routed to the right chaperone? How does the machine handle different growth rates? Here, we model proteostasis. We find that it can handle any arbitrary client protein, that it spends the least energy on least sick proteins, and that the cell produces just enough chaperone to keep the proteome folded but no more. (See pp. E2654–E2661.)
Large-scale identification of coevolution signals across homo-oligomeric protein interfaces by direct coupling analysis
Guido Uguzzoni, Shalini John Lovis, Francesco Oteri, Alexander Schug, Hendrik Szurmant, and Martin Weigt
Protein–protein interactions are important to all facets of life, but their experimental and computational characterization is arduous and frequently of uncertain outcome. The current study demonstrates both the power and limitation to study protein interactions by utilizing sophisticated statistical inference technology to derive protein contacts from available sequence databases, more precisely from the coevolution between residues, that are in contact across the interaction interface of two proteins. By studying homo-oligomeric protein interactions, the current study expands from anecdotal evidence of the performance of this technology to systematic evidence of its value across close to 2,000 interacting protein families. (See pp. E2662–E2671.)
Fission yeast myosin I facilitates PI(4,5)P2-mediated anchoring of cytoplasmic dynein to the cortex
Jerrin Mathew Thankachan, Stephen Sukumar Nuthalapati, Nireekshit Addanki Tirumala, and Vaishnavi Ananthanarayanan
Molecular motors perform a variety of functions such as muscle movement and nuclear positioning during cell division. One such motor protein, cytoplasmic dynein, is responsible for oscillations of the nucleus during meiosis of the unicellular eukaryote, fission yeast. In this study, we used genetics, live-cell fluorescence microscopy, and image processing to identify the key players that keep dynein at the cortex while it performs the function of back-and-forth nuclear movement by producing force on the microtubule. We discovered that the membrane phospholipid PI(4,5)P2 and, surprisingly, the myosin I motor Myo1 are both indispensable for nuclear oscillations in fission yeast. This study thus demonstrates one of the few instances of interplay between different classes of motor proteins in the cell. (See pp. E2672–E2681.)
Toll pathway is required for wound-induced expression of barrier repair genes in the Drosophila epidermis
Amalia Capilla, Dmitry Karachentsev, Rachel A. Patterson, Anita Hermann, Michelle T. Juarez, and William McGinnis
After breaks in animal epidermal barriers, repair genes are activated in the cells adjacent to wound sites that help regenerate the barrier. The fruit fly Drosophila melanogaster is a favorable genetic system to find molecular detection systems that sense wounds and activate repair genes. In this paper, we find that the Toll signaling pathway, including the extracellular ligand Spätzle, the Toll receptor, and the Dif transcription factor, form a detection system to sense broken epidermis and then activate regeneration genes. The Toll pathway thus is involved not only in the activation of genes involved in fighting microbial invasion after epidermal breaks, but also in the activation of genes that regenerate epidermal barrier function. (See pp. E2682–E2688.)
AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans
Emilie Demoinet, Shaolin Li, and Richard Roy
Following periods of famine, a reproducible spectrum of disorders often manifest long after the period of starvation. Curiously, many of these diseases arise in individuals that have no apparent genetic history of the disorder, although they do correlate with specific epigenetic modifications. We used Caenorhabditis elegans as a model to understand how acute periods of starvation might result in physiological or developmental consequences in a single generation or over multiple generations following the initial period of stress. Our data suggest that the AMP-activated protein kinase, an enzyme that mediates metabolic adjustment during starvation, is required to block germ-line gene expression during these conditions. In its absence the inappropriate activation of germ-line transcription results in sterility and transgenerational reproductive defects. (See pp. E2689–E2698.)
Injury-stimulated and self-restrained BMP signaling dynamically regulates stem cell pool size during Drosophila midgut regeneration
Aiguo Tian, Bing Wang, and Jin Jiang
Adult stem cells maintain tissue integrity by producing new cells to replenish damaged cells during tissue homeostasis and in response to injury. Using Drosophila adult midgut as a model we show that midgut injury elicited by chemical feeding or bacterial infection stimulates the production of two bone morphogenetic protein (BMP) ligands (Dpp and Gbb) that are critical for the expansion of the intestinal stem cell (ISC) population and midgut regeneration. Interestingly, we find that BMP expression is inhibited by BMP signaling itself, and this autoinhibition is required for resetting ISC pool size to the homeostatic level after tissue repair. Our study suggests that transient expansion of the stem cell population through the dynamic regulation of niche signals serves as a strategy for regeneration. (See pp. E2699–E2708.)
Hormone and receptor interplay in the regulation of mosquito lipid metabolism
Xueli Wang, Yuan Hou, Tusar T. Saha, Gaofeng Pei, Alexander S. Raikhel, and Zhen Zou
Mosquitoes require a blood meal to reproduce and by blood feeding transmit some of the most dangerous human diseases. Female mosquitoes have extremely high metabolism, and the elucidation of regulatory pathways coordinating reproductive and metabolic events is essential. RNAi of the juvenile hormone receptor Methoprene-tolerant (Met) promoted triacylglycerol (TAG) catabolism and β-oxidation and diminished TAG levels, whereas ecdysone receptor (EcR) RNAi had an opposite effect. Hepatocyte nuclear factor 4 (HNF4) directly regulated TAG catabolism and β-oxidation genes, and its RNAi silencing phenocopied EcR RNAi. The expression of the HNF4 gene was downregulated by Met and activated by EcR and Target of rapamycin. Thus, HNF4 mediates hormonal and nutritional signaling of lipid metabolism regulation in reproducing female Aedes aegypti mosquitoes. (See pp. E2709–E2718.)
Multitrait successional forest dynamics enable diverse competitive coexistence
Daniel S. Falster, Åke Brännström, Mark Westoby, and Ulf Dieckmann
Walking through any forest, one is struck by the variety of plant forms coexisting. Given that all plants compete for the same basic resources, why is there not a single winner? Our study shows that when key ingredients common to all forests are accounted for—including disturbance events, competition for light, and two widely observed trait-based tradeoffs—models of niche differentiation predict forests of considerably greater diversity than was previously thought possible. In particular, our model accurately predicts the proliferation of species occupying niche space in low light, a feature of tropical forests that motivated the so-called neutral theory of biodiversity and biogeography. The presented results thereby provide a platform for understanding diversity in forests worldwide. (See pp. E2719–E2728.)
Osmolality/salinity-responsive enhancers (OSREs) control induction of osmoprotective genes in euryhaline fish
Xiaodan Wang and Dietmar Kültz
Salinity stress is common in many environments and is predicted to intensify. Such stress increases the expression of numerous genes in fish, but the corresponding regulatory mechanisms are unknown. Our study provides a toolkit for discovering and functionally validating cis-regulatory elements (CREs) that control inducible gene expression in fish. This toolkit was used for experimental identification of the first osmotic/salinity-responsive CREs in fish (OSRE1). Our findings greatly empower novel approaches for deciphering fish osmosensory signaling and gene regulatory networks. Because sequence variation in inducible CREs is critical for the evolution of stress tolerance, knowledge of osmolality/salinity-responsive enhancers is critical for revealing the evolution and function of regulatory networks responsible for euryhalinity of fish. (See pp. E2729–E2738.)
Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice
Danny Halim, Michael P. Wilson, Daniel Oliver, Erwin Brosens, Joke B. G. M. Verheij, Yu Han, Vivek Nanda, Qing Lyu, Michael Doukas, Hans Stoop, Rutger W. W. Brouwer, Wilfred F. J. van IJcken, Orazio J. Slivano, Alan J. Burns, Christine K. Christie, Karen L. de Mesy Bentley, Alice S. Brooks, Dick Tibboel, Suowen Xu, Zheng Gen Jin, Tono Djuwantono, Wei Yan, Maria M. Alves, Robert M. W. Hofstra, and Joseph M. Miano
Rare recessive monogenic diseases are often found in isolated populations. In one such population, we identified a child carrying a homozygous nonsense mutation in an understudied smooth muscle-restricted gene called Leiomodin1 (LMOD1). Heterozygous parents showed no disease; however, the child died shortly after birth from a rare condition known as megacystis microcolon intestinal hypoperistalsis syndrome. A mouse model with a similar Lmod1 mutation, engineered with CRISPR-Cas9 genome editing, exhibited the same gastrointestinal and urinary bladder phenotypes as seen in the newborn child. Phenotyping revealed insights into the underlying cause of the disease. Results demonstrate the conserved function of LMOD1 in human and mice and the importance of this protein in the molecular regulation of contractility in visceral smooth muscle cells. (See pp. E2739–E2747.)
Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ
Joseph S. Ainscough, Tom Macleod, Dennis McGonagle, Rosella Brakefield, Jens M. Baron, Ade Alase, Miriam Wittmann, and Martin Stacey
IL-36γ is a potent cytokine that drives and orchestrates inflammation. It is strongly expressed at barrier tissues such as the skin and thus is particularly relevant to inflammatory diseases that affect these tissues, including psoriasis. IL-36γ is expressed as an inactive precursor that requires precise N-terminal truncation for activation. In these investigations, we demonstrate that cathepsin S is the major IL-36γ–activating protease expressed by barrier tissues. Moreover, we show that both cathepsin S and IL-36γ are strongly up-regulated in psoriatic inflammation. These findings are important as they both identify the mechanism of IL-36γ activation and highlight that this mechanism may play a central role in the development of psoriatic inflammation. (See pp. E2748–E2757.)
Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate
Alexey V. Kostarnoy, Petya G. Gancheva, Bernd Lepenies, Amir I. Tukhvatulin, Alina S. Dzharullaeva, Nikita B. Polyakov, Daniil A. Grumov, Daria A. Egorova, Andrey Y. Kulibin, Maxim A. Bobrov, Ekaterina A. Malolina, Pavel A. Zykin, Andrey I. Soloviev, Evgeniy Riabenko, Diana V. Maltseva, Dmitry A. Sakharov, Alexander G. Tonevitsky, Lyudmila V. Verkhovskaya, Denis Y. Logunov, Boris S. Naroditsky, and Alexander L. Gintsburg
Post-traumatic sterile inflammation is the first necessary step of wound healing. In addition, sterile inflammation underlies the pathogenesis of a multitude of common diseases, such as allergies and autoimmune diseases. The molecular mechanisms underlying sterile inflammation are still not fully understood. Here, we show that the receptor Mincle (Clec4e), the expression of which is highly induced in the skin in response to damage, recognizes cholesterol sulfate, a molecule that is abundant in the epidermal layer of the skin, subsequently inducing a pro-inflammatory response. We also identify a role for Mincle as a driving component in the pathogenesis of allergic skin inflammation. The results demonstrate a previously unconsidered important role of Mincle in mediating sterile inflammation. (See pp. E2758–E2765.)
Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo
Yaw Asare, Miriam Ommer, Florence. A. Azombo, Setareh Alampour-Rajabi, Marieke Sternkopf, Maryam Sanati, Marion J. Gijbels, Corinna Schmitz, Dzmitry Sinitski, Pathricia V. Tilstam, Hongqi Lue, André Gessner, Denise Lange, Johannes A. Schmid, Christian Weber, Martin Dichgans, Joachim Jankowski, Ruggero Pardi, Menno P. J. de Winther, Heidi Noels, and Jürgen Bernhagen
Atherosclerosis is an inflammatory condition of the artery wall and main cause of myocardial infarction and stroke. Inflammatory processes evoking atherogenic lesions involve NF‐κB–dependent endothelial-cell activation and monocyte/macrophage recruitment. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) subunit 5 (CSN5) and the CSN control cullin/RING E3 ligase-dependent degradation of cell-cycle regulators and inhibitor of κB‐α by cleaving neural precursor cell-expressed, developmentally down-regulated-8 (NEDD8) from cullins. CSN5 promotes tumorigenesis in humans. We generated a conditional KO mouse in which macrophage/granulocyte-CSN5 is deleted. We show that CSN5 suppresses macrophage inflammation and that mice lacking myeloid CSN5 develop larger atherosclerotic lesions. The NEDDylation inhibitor MLN4924 attenuates early atherosclerosis and inhibits inflammation in macrophages and endothelial cells. With MLN4924 in clinical trials, deNEDDylation approaches may qualify as therapeutics to reduce early-stage atherogenesis. (See pp. E2766–E2775.)
Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells
Giuliana P. Mognol, Roberto Spreafico, Victor Wong, James P. Scott-Browne, Susan Togher, Alexander Hoffmann, Patrick G. Hogan, Anjana Rao, and Sara Trifari
Cancer cells can be recognized and attacked by CD8+ cytolytic T cells, but tumor-infiltrating T cells often become functionally incompetent (“exhausted”) and fail to destroy tumor cells. We show that T-cell exhaustion requires antigen recognition by tumor-infiltrating T cells. By examining the transcriptional and chromatin accessibility profiles of antigen-reactive and -unreactive tumor-infiltrating cells, we confirm our previous conclusion that the transcription factor NFAT promotes CD8+ T-cell exhaustion and we identify Nr4a transcription factors as new targets for future investigation. We show that anti–PD-L1 treatment, a clinically relevant checkpoint blockade therapy that counteracts T-cell exhaustion, has modest but functionally important effects on gene expression in exhausted cells, without causing major changes in patterns of chromatin accessibility. (See pp. E2776–E2785.)
Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways
Lisa P. Daley-Bauer, Linda Roback, Lynsey N. Crosby, A. Louise McCormick, Yanjun Feng, William J. Kaiser, and Edward S. Mocarski
Caspase-8–mediated apoptotic and receptor-interacting protein (RIP)-dependent necroptotic signaling pathways are recognized host defense mechanisms that act by eliminating virus-infected cells. Cytomegalovirus-encoded inhibitors of apoptosis and necroptosis sustain infection and pathogenesis by preventing specific programmed cell death pathways. In the absence of viral inhibitors, combined apoptotic–necroptotic cell death signaling halts infection, preventing the virus from gaining a foothold in the host. We describe natural cooperation between apoptosis and necroptosis pathways in macrophages and within the host, resulting in robust proinflammatory cytokine responses not observed when infected cells die by either apoptosis or necroptosis alone. Thus, apoptosis combined with necroptosis serves a dual role in limiting herpesvirus persistence in the host. (See pp. E2786–E2795.)