PNAS PLUS NSPLUS PNAS

PNAS Plus Significance Statements

Effect of material flexibility on the thermodynamics (PPAR) δ concomitant with distinct conformational and kinetics of hydrophobically induced changes in the receptor, key to therapeutic modu- evaporation of water lation of lipid catabolism, transport, and storage. Y. Elia Altabet, Amir Haji-Akbari ( ), These studies reveal the subtle interplay between li- and Pablo G. Debenedetti gand configuration and chemistry coupled to modu- δ – The evaporation of water in hydrophobic confinement lation of PPAR structural dynamics. This set of structure is important for the formation and function of both activity relationships (SARs) guide synthetic ligand natural and synthetic hydrophobic self-assemblies. designs necessary to refine therapeutic leads for δ Using advanced computational techniques, we find temporally and spatially regulating PPAR during the that the thermodynamic and kinetic stability of water course of metabolic disease onset and progression. – in hydrophobic confinement is extremely sensitive to (See pp. E2563 E2570.) the flexibility of the confining material. In the context of engineered systems, this work suggests that the Biological regulation of atmospheric chemistry mechanical properties of the building blocks in a self- en route to planetary oxygenation assembled system are a crucial design consideration. Gareth Izon, Aubrey L. Zerkle, Kenneth H. Williford, James With respect to biophysical phenomena, it suggests Farquhar, Simon W. Poulton, and Mark W. Claire that small changes in flexibility can induce switch-like It has been proposed that enhanced methane fluxes to responses such as the opening and closing of mem- Earth’s early atmosphere could have altered atmo- brane channels and the conversion between active spheric chemistry, initiating a hydrocarbon-rich haze and inactive states in receptors, both of which are reminiscent of Saturn’s moon Titan. The occurrence, – common drug targets. (See pp. E2548 E2555.) cause, and significance of haze development, how- ever, remain unknown. Here, we test and refine the Electron transfer between anatase TiO2 and “haze hypothesis” by combining an ultra-high-resolu- an O2 molecule directly observed by atomic force microscopy tion sulfur- and carbon-isotope dataset with photo- chemical simulations to reveal the structure and timing Martin Setvin, Jan Hulva, Gareth S. Parkinson, Michael of haze development. These data suggest that haze Schmid, and Ulrike Diebold persisted for ∼1 million years, requiring a sustained Molecular oxygen is an inert species, unable to enter biological driver. We propose that enhanced atmo- chemical reactions. Activation occurs through the spheric CH4, implied by the presence of haze, could acceptance of an extra electron; this catalytic step have had a significant impact on the escape of hy- plays a major role in applications such as heteroge- drogen from the atmosphere, effectively contributing neous catalysis and fuel cells. It is also used by all to the terminal oxidation of Earth’s surficial environ- living organisms. We show that the two different ments ∼2.4 billion years ago. (See pp. E2571–E2579.) charge states of O2 can be easily distinguished by atomic force microscopy (AFM). We directly injected Optimal run-and-tumble–based transportation or removed electrons into/from the O2 molecule by of a Janus particle with active steering the AFM tip, switching the O reactivity. These results 2 Tomoyuki Mano, Jean-Baptiste Delfau, Junichiro Iwasawa, open new possibilities for studying catalytic and and Masaki Sano photocatalytic processes. (See pp. E2556–E2562.) Commanding the swimming of micrometric objects Structural basis for specific ligation of the subjected to thermal agitation is always challenging for peroxisome proliferator-activated receptor δ both artificial and living systems. Now, artificial swim- Chyuan-Chuan Wu, Thomas J. Baiga, Michael Downes, mers can be designed with self-propelling force that James J. La Clair, Annette R. Atkins, Stephane B. Richard, can be tuned at will. However, orienting such small Weiwei Fan, Theresa A. Stockley-Noel, Marianne E. Bowman, particles to an arbitrary direction requires counter- Joseph P. Noel, and Ronald M. Evans balancing the random rotational diffusion. Here, we Clinical treatments for metabolic diseases rely on introduce a simple concept to reorient artificial swim- agents with high selectivity to specific targets often mers, granting them a motion similar to the run-and- within a class of structurally and functionally related tumbling behavior of Escherichia coli.Weshowitusing proteins. In this paper, we uncover physical and chem- Janus particles with asymmetric surface coating and ical features governing selective small-molecule bind- moving under an ac electric field. Moreover, we de- ing to peroxisome proliferator-activated receptor termine the optimal strategy and compare it with

3292–3296 | PNAS | March 28, 2017 | vol. 114 | no. 13 www.pnas.org/cgi/doi/10.1073/pnas.ss11413 Downloaded by guest on September 27, 2021 biological swimmers. Our results encourage additional in- instead the resulting photoproduct is thermally reisomerized back vestigation into dynamical behavior of colloidal particles as to its inactive state, abrogating the necessity for a complex reti- well as application to microscopic devices. (See pp. E2580–E2589.) noid cycle to renew its chromophore. This photocyclic behavior of Rh6mr opens up several avenues for using optogenetic tools Cross-cousin marriage among the Yanomamö shows based on vertebrate Rhs. (See pp. E2608–E2615.) evidence of parent–offspring conflict and mate competition between brothers Phytosphingosine degradation pathway includes fatty acid α Napoleon A. Chagnon, Robert F. Lynch, Mary K. Shenk, Raymond Hames, -oxidation reactions in the endoplasmic reticulum and Mark V. Flinn Takuya Kitamura, Naoya Seki, and Akio Kihara Cross-cousin marriage (i.e., marriage with the offspring of a par- Although the synthetic pathway of phytosphingosine is already ent’s opposite-sex sibling) is the most common preferred mar- known, its degradation pathway has remained unclear. In the riage arrangement across cultures. Despite intense investigation, present study, we reveal the entire phytosphingosine degrada- the origin and adaptive function of this marriage prescription tion pathway, where fatty acid α-oxidation is involved. We show have not been resolved. An analysis of the fitness consequences that the Sjögren–Larsson syndrome-causative gene ALDH3A2 of marriages in the Yanomamö—a tribal society in the Amazon— and HACL2 (2-hydroxyacyl-CoA lyase 2) are involved in the fatty shows that parents and brothers achieve higher fitness outcomes acid α-oxidation reactions as an aldehyde dehydrogenase and a when their respective children and sisters marry more closely 2-hydroxy acyl-CoA lyase, respectively. Our findings are impor- related individuals. Meanwhile, the spouses and offspring pro- tant for understanding the molecular mechanism of phytos- duced by these unions have lower fitness. These findings suggest phingosine/sphingolipid homeostasis. HACL2 is localized in the that cross-cousin marriage prescriptions and taboos against endoplasmic reticulum, indicating that fatty acid α-oxidation oc- marrying parallel cousins owe their origin to parent–offspring curs in the endoplasmic reticulum in mammals, in addition to the conflict through parental control of marriage and competition α-oxidation already known to occur in peroxisomes. (See pp. between same-sex siblings. (See pp. E2590–E2597.) E2616–E2623.)

Morphological features of IFN-γ–stimulated mesenchymal Structure-guided SCHEMA recombination generates stromal cells predict overall immunosuppressive capacity diverse chimeric channelrhodopsins Matthew W. Klinker, Ross A. Marklein, Jessica L. Lo Surdo, Cheng-Hong Claire N. Bedbrook, Austin J. Rice, Kevin K. Yang, Xiaozhe Ding, Siyuan Wei, and Steven R. Bauer Chen, Emily M. LeProust, Viviana Gradinaru, and Frances H. Arnold Substantial evidence exists demonstrating the immunosup- Critical for regulating cell function, integral membrane proteins pressive function of mesenchymal stromal cells (MSCs), but in- (MPs) are key engineering targets. MP engineering is limited consistent clinical results suggest that better understanding of because these proteins are difficult to express with proper plasma MSC-mediated immunosuppression and identification of fea- membrane localization in heterologous systems. We investigate tures predictive of immunosuppressive capacity would advance the expression, localization, and light-induced behavior of the MSC-based therapeutics. In this work, we present a robust an- light-gated MP channel, channelrhodopsin (ChR), because of its alytical approach to quantify the immunosuppressive capacity utility in studying neuronal circuitry. We used structure-guided of MSCs by integrating high-dimensional flow cytometry data SCHEMA recombination to generate libraries of chimeric ChRs from multiple experimental conditions into a single measure of that are diverse in sequence yet still capable of efficient ex- immunosuppressive capacity. Additionally, we identified mor- pression, localization, and useful light-induced functionality. phological features of MSCs that predicted immunosuppressive The conservative nature of recombination generates unique capacity, as well as the magnitude of IFN-γ–mediated immuno- protein sequences that tend to fold and function. Recombination is suppression enhancement. These improved methods of MSC also innovative: chimeric ChRs can outperform their parents or characterization could be used to identify MSC preparations even exhibit properties not known in natural ChRs. (See pp. with desired immunosuppressive capacity, as well as screen for E2624–E2633.) pretreatments that enhance their immunosuppressive function. – (See pp. E2598 E2607.) Multisite aggregation of p53 and implications for drug rescue Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism GuoZhen Wang and Alan R. Fersht Sahil Gulati, Beata Jastrzebska, Surajit Banerjee, Ángel L. Placeres, Destabilized mutants of the tumor suppressor p53 are inactivated Przemyslaw Miszta, Songqi Gao, Karl Gunderson, Gregory P. Tochtrop, by self-aggregation in a substantial number of tumors and may Sławomir Filipek, Kota Katayama, Philip D. Kiser, Muneto Mogi, Phoebe L. also coaggregate with and inactivate WT p53 and family mem- Stewart, and Krzysztof Palczewski bers. We found in vitro that self-aggregation proceeded via a Vertebrate rhodopsin (Rh) has been a model system for many G network of multiple aggregation-prone sites in p53, and in- protein-coupled receptors for over a decade. However, due to its hibition of an individual site did not inhibit aggregation. Never- thus-far limited repertoire of active ligands, its use in assisting the theless, peptides designed to be complementary to various development of new therapeutic modalities and drugs has been aggregation sequences and inhibit their polymerization can limited. This study elucidates a photocyclic G protein activation specifically kill cancer cells and be potential anticancer drugs. We by Rh bound with a six-carbon ring retinal (Rh6mr), and thus found that those peptides can also function by p53-independent broadens the diversity of such Rh signaling modulators. Rh6mr routes in cancer cell cultures, implying further therapeutic targets. does not release its chromophore after light activation, but (See pp. E2634–E2643.)

PNAS | March 28, 2017 | vol. 114 | no. 13 | 3293 Downloaded by guest on September 27, 2021 Phosphorylation-induced conformational dynamics in an Fission yeast myosin I facilitates PI(4,5)P2-mediated intrinsically disordered protein and potential role anchoring of cytoplasmic dynein to the cortex in phenotypic heterogeneity Jerrin Mathew Thankachan, Stephen Sukumar Nuthalapati, Nireekshit Prakash Kulkarni, Mohit Kumar Jolly, Dongya Jia, Steven M. Mooney, Addanki Tirumala, and Vaishnavi Ananthanarayanan Ajay Bhargava, Luciane T. Kagohara, Yihong Chen, Pengyu Hao, Yanan Molecular motors perform a variety of functions such as muscle He, Robert W. Veltri, Alexander Grishaev, Keith Weninger, Herbert Levine, movement and nuclear positioning during cell division. One such and John Orban motor protein, cytoplasmic dynein, is responsible for oscillations of The onset of androgen resistance is a major impediment in the nucleus during meiosis of the unicellular eukaryote, fission treating prostate cancer (PCa). However, the underlying mo- yeast. In this study, we used genetics, live-cell fluorescence mi- lecular mechanisms are not fully understood. Here, we integrate croscopy, and image processing to identify the key players that multiple biophysical approaches that report conformational keep dynein at the cortex while it performs the function of back- preferences of the intrinsically disordered protein (IDP) Prostate- and-forth nuclear movement by producing force on the microtu- Associated Gene 4 (PAGE4) with human cancer biology and bule. We discovered that the membrane phospholipid PI(4,5)P2 nonlinear dynamics. Based on our biophysical, biochemical, and and, surprisingly, the myosin I motor Myo1 are both indispensable cellular data, a mathematical model is presented that suggests a for nuclear oscillations in fission yeast. This study thus demon- mechanism by which phosphorylation-induced conformational strates one of the few instances of interplay between different changes in PAGE4 can switch from an androgen-dependent classes of motor proteins in the cell. (See pp. E2672–E2681.) phenotype to an androgen-independent phenotype in PCa cells. The study underscores how IDPs that engage in multiple Toll pathway is required for wound-induced expression of “ ” promiscuous interactions due to their conformational dy- barrier repair genes in the Drosophila epidermis namics when overexpressed or aberrantly expressed can sto- Amalia Capilla, Dmitry Karachentsev, Rachel A. Patterson, Anita Hermann, chastically orchestrate phenotypic heterogeneity in PCa. (See Michelle T. Juarez, and William McGinnis pp. E2644–E2653.) After breaks in animal epidermal barriers, repair genes are activated in Bacterial proteostasis balances energy and chaperone the cells adjacent to wound sites that help regenerate the barrier. The utilization efficiently fruit fly Drosophila melanogaster is a favorable genetic system to find molecular detection systems that sense wounds and activate repair Mantu Santra, Daniel W. Farrell, and Ken A. Dill genes. In this paper, we find that the Toll signaling pathway, including A cell’s proteins must be properly folded. Therefore, cells have the extracellular ligand Spätzle, the Toll receptor, and the Dif tran- chaperones that help other proteins, their clients, fold and not scription factor, form a detection system to sense broken epidermis aggregate. The machinery is like a hospital: it assesses the and then activate regeneration genes. The Toll pathway thus is in- “sickness” of the patient (finds improperly folded proteins), sends volved not only in the activation of genes involved in fighting micro- the patient to the right doctor (sorts the protein to the right bial invasion after epidermal breaks, but also in the activation of genes chaperone), and cures the disease (folds or disaggregates the that regenerate epidermal barrier function. (See pp. E2682–E2688.) protein). How are sick proteins recognized and routed to the right chaperone? How does the machine handle different growth AMPK blocks starvation-inducible transgenerational rates? Here, we model proteostasis. We find that it can handle defects in Caenorhabditis elegans any arbitrary client protein, that it spends the least energy on Emilie Demoinet, Shaolin Li, and Richard Roy least sick proteins, and that the cell produces just enough Following periods of famine, a reproducible spectrum of disorders chaperone to keep the proteome folded but no more. (See pp. often manifest long after the period of starvation. Curiously, many E2654–E2661.) of these diseases arise in individuals that have no apparent genetic Large-scale identification of coevolution signals across history of the disorder, although they do correlate with specific homo-oligomeric protein interfaces by direct epigenetic modifications. We used Caenorhabditis elegans as a coupling analysis model to understand how acute periods of starvation might result in physiological or developmental consequences in a single genera- Guido Uguzzoni, Shalini John Lovis, Francesco Oteri, Alexander Schug, Hendrik Szurmant, and Martin Weigt tion or over multiple generations following the initial period of stress. Our data suggest that the AMP-activated protein kinase, – Protein protein interactions are important to all facets of life, an enzyme that mediates metabolic adjustment during starva- but their experimental and computational characterization is tion, is required to block germ-line gene expression during arduous and frequently of uncertain outcome. The current study these conditions. In its absence the inappropriate activation of demonstrates both the power and limitation to study protein germ-line transcription results in sterility and transgenerational interactions by utilizing sophisticated statistical inference tech- reproductive defects. (See pp. E2689–E2698.) nology to derive protein contacts from available sequence da- tabases, more precisely from the coevolution between residues, Injury-stimulated and self-restrained BMP signaling that are in contact across the interaction interface of two pro- dynamically regulates stem cell pool size during teins. By studying homo-oligomeric protein interactions, the Drosophila midgut regeneration current study expands from anecdotal evidence of the perfor- mance of this technology to systematic evidence of its value Aiguo Tian, Bing Wang, and Jin Jiang across close to 2,000 interacting protein families. (See pp. Adult stem cells maintain tissue integrity by producing new cells to E2662–E2671.) replenish damaged cells during tissue homeostasis and in response

3294 | www.pnas.org/cgi/doi/10.1073/pnas.ss11413 Downloaded by guest on September 27, 2021 to injury. Using Drosophila adultmidgutasamodelweshowthat revealing the evolution and function of regulatory networks re- midgut injury elicited by chemical feeding or bacterial infection sponsible for euryhalinity of fish. (See pp. E2729–E2738.) stimulates the production of two bone morphogenetic protein (BMP) ligands (Dpp and Gbb) that are critical for the expansion of the in- Loss of LMOD1 impairs smooth muscle cytocontractility testinal stem cell (ISC) population and midgut regeneration. In- and causes megacystis microcolon intestinal terestingly, we find that BMP expression is inhibited by BMP hypoperistalsis syndrome in humans and mice signaling itself, and this autoinhibition is required for resetting ISC Danny Halim, Michael P. Wilson, Daniel Oliver, Erwin Brosens, Joke B. G. M. pool size to the homeostatic level after tissue repair. Our study Verheij, Yu Han, Vivek Nanda, Qing Lyu, Michael Doukas, Hans Stoop, suggests that transient expansion of the stem cell population through 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, the dynamic regulation of niche signals serves as a strategy Dick Tibboel, Suowen Xu, Zheng Gen Jin, Tono Djuwantono, Wei Yan, for regeneration. (See pp. E2699–E2708.) Maria M. Alves, Robert M. W. Hofstra, and Joseph M. Miano Rare recessive monogenic diseases are often found in isolated Hormone and receptor interplay in the regulation of populations. In one such population, we identified a child carry- mosquito lipid metabolism ing a homozygous nonsense mutation in an understudied smooth Xueli Wang, Yuan Hou, Tusar T. Saha, Gaofeng Pei, Alexander S. Raikhel, muscle-restricted gene called Leiomodin1 (LMOD1). Heterozy- and Zhen Zou gous parents showed no disease; however, the child died shortly Mosquitoes require a blood meal to reproduce and by blood after birth from a rare condition known as megacystis microcolon feeding transmit some of the most dangerous human diseases. intestinal hypoperistalsis syndrome. A mouse model with a similar Female mosquitoes have extremely high metabolism, and the elu- Lmod1 mutation, engineered with CRISPR-Cas9 genome editing, cidation of regulatory pathways coordinating reproductive and exhibited the same gastrointestinal and urinary bladder phenotypes metabolic events is essential. RNAi of the juvenile hormone receptor as seen in the newborn child. Phenotyping revealed insights into the Methoprene-tolerant (Met) promoted triacylglycerol (TAG) catabo- underlying cause of the disease. Results demonstrate the conserved lism and β-oxidation and diminished TAG levels, whereas ecdysone function of LMOD1 in human and mice and the importance of this receptor (EcR) RNAi had an opposite effect. Hepatocyte nuclear protein in the molecular regulation of contractility in visceral smooth factor 4 (HNF4) directly regulated TAG catabolism and β-oxidation muscle cells. (See pp. E2739–E2747.) genes, and its RNAi silencing phenocopied EcR RNAi. The expres- sion of the HNF4 gene was downregulated by Met and activated by Cathepsin S is the major activator of the EcR and Target of rapamycin. Thus, HNF4 mediates hormonal and psoriasis-associated proinflammatory cytokine IL-36γ nutritional signaling of lipid metabolism regulation in reproducing Joseph S. Ainscough, Tom Macleod, Dennis McGonagle, Rosella Brakefield, female Aedes aegypti mosquitoes. (See pp. E2709–E2718.) Jens M. Baron, Ade Alase, Miriam Wittmann, and Martin Stacey IL-36γ is a potent cytokine that drives and orchestrates inflammation. Multitrait successional forest dynamics enable diverse It is strongly expressed at barrier tissues such as the skin and thus is competitive coexistence particularly relevant to inflammatory diseases that affect these tis- Daniel S. Falster, Åke Brännström, Mark Westoby, and Ulf Dieckmann sues, including psoriasis. IL-36γ is expressed as an inactive pre- Walking through any forest, one is struck by the variety of plant forms cursor that requires precise N-terminal truncation for activation. coexisting. Given that all plants compete for the same basic re- In these investigations, we demonstrate that cathepsin S is the sources, why is there not a single winner? Our study shows that when major IL-36γ–activating protease expressed by barrier tissues. key ingredients common to all forests are accounted for—including Moreover, we show that both cathepsin S and IL-36γ are strongly disturbance events, competition for light, and two widely observed up-regulated in psoriatic inflammation. These findings are im- trait-based tradeoffs—models of niche differentiation predict forests portant as they both identify the mechanism of IL-36γ activation of considerably greater diversity than was previously thought possible. and highlight that this mechanism may play a central role in the In particular, our model accurately predicts the proliferation of species development of psoriatic inflammation. (See pp. E2748–E2757.) occupying niche space in low light, a feature of tropical forests that motivated the so-called neutral theory of biodiversity and bio- Receptor Mincle promotes skin allergies and is capable of geography. The presented results thereby provide a platform for recognizing cholesterol sulfate understanding diversity in forests worldwide. (See pp. E2719–E2728.) Alexey V. Kostarnoy, Petya G. Gancheva, Bernd Lepenies, Amir I. Tukhvatulin, Alina S. Dzharullaeva, Nikita B. Polyakov, Daniil A. Grumov, Daria A. Egorova, Osmolality/salinity-responsive enhancers (OSREs) control Andrey Y. Kulibin, Maxim A. Bobrov, Ekaterina A. Malolina, Pavel A. Zykin, Andrey I. Soloviev, Evgeniy Riabenko, Diana V. Maltseva, Dmitry A. Sakharov, induction of osmoprotective genes in euryhaline fish Alexander G. Tonevitsky, Lyudmila V. Verkhovskaya, Denis Y. Logunov, Xiaodan Wang and Dietmar Kültz Boris S. Naroditsky, and Alexander L. Gintsburg Salinity stress is common in many environments and is predicted to Post-traumatic sterile inflammation is the first necessary step of wound intensify. Such stress increases the expression of numerous genes in healing. In addition, sterile inflammation underlies the pathogenesis fish, but the corresponding regulatory mechanisms are unknown. of a multitude of common diseases, such as allergies and auto- Our study provides a toolkit for discovering and functionally validat- immune diseases. The molecular mechanisms underlying sterile in- ing cis-regulatory elements (CREs) that control inducible gene ex- flammation are still not fully understood. Here, we show that the pression in fish. This toolkit was used for experimental identification of receptor Mincle (Clec4e), the expression of which is highly induced in the first osmotic/salinity-responsive CREs in fish (OSRE1). Our findings the skin in response to damage, recognizes cholesterol sulfate, a greatly empower novel approaches for deciphering fish osmosensory molecule that is abundant in the epidermal layer of the skin, sub- signaling and gene regulatory networks. Because sequence variation sequently inducing a pro-inflammatory response. We also identify a in inducible CREs is critical for the evolution of stress tolerance, role for Mincle as a driving component in the pathogenesis of allergic knowledge of osmolality/salinity-responsive enhancers is critical for skin inflammation. The results demonstrate a previously unconsidered

PNAS | March 28, 2017 | vol. 114 | no. 13 | 3295 Downloaded by guest on September 27, 2021 importantroleofMincleinmediating sterile inflammation. (See pp. incompetent (“exhausted”) and fail to destroy tumor cells. We E2758–E2765.) show that T-cell exhaustion requires antigen recognition by tumor-infiltrating T cells. By examining the transcriptional Inhibition of atherogenesis by the COP9 signalosome and chromatin accessibility profiles of antigen-reactive and subunit 5 in vivo -unreactive tumor-infiltrating cells, we confirm our previous + Yaw Asare, Miriam Ommer, Florence. A. Azombo, Setareh Alampour-Rajabi, conclusion that the transcription factor NFAT promotes CD8 Marieke Sternkopf, Maryam Sanati, Marion J. Gijbels, Corinna Schmitz, T-cell exhaustion and we identify Nr4a transcription factors as Dzmitry Sinitski, Pathricia V. Tilstam, Hongqi Lue, André Gessner, new targets for future investigation. We show that anti–PD-L1 Denise Lange, Johannes A. Schmid, Christian Weber, Martin Dichgans, Joachim Jankowski, Ruggero Pardi, Menno P. J. de Winther, Heidi Noels, treatment, a clinically relevant checkpoint blockade therapy and Jürgen Bernhagen that counteracts T-cell exhaustion, has modest but functionally Atherosclerosis is an inflammatory condition of the artery wall and important effects on gene expression in exhausted cells, with- main cause of myocardial infarction and stroke. Inflammatory out causing major changes in patterns of chromatin accessibility. – processes evoking atherogenic lesions involve NF‐κB–dependent (See pp. E2776 E2785.) endothelial-cell activation and monocyte/macrophage recruitment. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) Mouse cytomegalovirus M36andM45deathsuppressors subunit 5 (CSN5) and the CSN control cullin/RING E3 ligase- cooperate to prevent inflammation resulting from dependent degradation of cell-cycle regulators and inhibitor of κB‐α antiviral programmed cell death pathways by cleaving neural precursor cell-expressed, developmentally down- regulated-8 (NEDD8) from cullins. CSN5 promotes tumorigenesis in Lisa P. Daley-Bauer, Linda Roback, Lynsey N. Crosby, A. Louise McCormick, Yanjun Feng, William J. Kaiser, and Edward S. Mocarski humans. We generated a conditional KO mouse in which macro- phage/granulocyte-CSN5 is deleted. We show that CSN5 suppresses Caspase-8–mediated apoptotic and receptor-interacting pro- macrophage inflammation and that mice lacking myeloid CSN5 tein (RIP)-dependent necroptotic signaling pathways are rec- develop larger atherosclerotic lesions. The NEDDylation inhibitor ognized host defense mechanisms that act by eliminating virus- MLN4924 attenuates early atherosclerosis and inhibits inflammation infected cells. Cytomegalovirus-encoded inhibitors of apoptosis in macrophages and endothelial cells. With MLN4924 in clinical and necroptosis sustain infection and pathogenesis by pre- trials, deNEDDylation approaches may qualify as therapeutics to venting specific programmed cell death pathways. In the ab- reduce early-stage atherogenesis. (See pp. E2766–E2775.) sence of viral inhibitors, combined apoptotic–necroptotic cell death signaling halts infection, preventing the virus from gain- + Exhaustion-associated regulatory regions in CD8 ing a foothold in the host. We describe natural cooperation tumor-infiltrating T cells between apoptosis and necroptosis pathways in macrophages Giuliana P. Mognol, Roberto Spreafico, Victor Wong, James P. Scott-Browne, and within the host, resulting in robust proinflammatory cyto- Susan Togher, Alexander Hoffmann, Patrick G. Hogan, Anjana Rao, kine responses not observed when infected cells die by either and Sara Trifari apoptosis or necroptosis alone. Thus, apoptosis combined with + Cancer cells can be recognized and attacked by CD8 cytolytic necroptosis serves a dual role in limiting herpesvirus persistence T cells, but tumor-infiltrating T cells often become functionally in the host. (See pp. E2786–E2795.)

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