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First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor (2017)

Moody, James D. ; Levy, Shiri ; Mathieu, Julie ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2017; 114(38): 10125-10130. Published 2017 Sep 01. doi: 10.1073/pnas.1706907114.

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Publication Date: 2017-09-01

Description: The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate recognition functions of PRC2 are coupled by binding of the N-terminal helix of the Ezh2 methylase to an extended groove on the EED trimethyl lysine binding subunit. Disrupting PRC2 function can in principle be achieved by blocking this single interaction, but there are few approaches for blocking specific protein–protein interactions in living cells and organisms. Here, we describe the computational design of proteins that bind to the EZH2 interaction site on EED with subnanomolar affinity in vitro and form tight and specific complexes with EED in living cells. Induction of the EED binding proteins abolishes H3K27 methylation in human embryonic stem cells (hESCs) and at all but the earliest stage blocks self-renewal, pinpointing the first critical repressive H3K27me3 marks in development.

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Electronic ISSN: 1091-6490

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First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor [Developmental Biology] (2017)

James D. Moody, Shiri Levy, Julie Mathieu, Yalan Xing, Woojin Kim, Cheng Dong, Wolfram Tempel, Aaron M. Robitaille, Luke T. Dang, Amy Ferreccio, Damien Detraux, Sonia Sidhu, Licheng Zhu, Lauren Carter, Chao Xu, Cristina Valensisi, Yuliang Wang, R. David Hawkins, Jinrong Min, Randall T. Moon, Stuart H. Orkin, David Baker, Hannele Ruohola-Baker

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences

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Publication Date: 2017-09-20

Description: The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate...

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Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis (2016)

Kudinov, Alexander E. ; Deneka, Alexander ; Nikonova, Anna S. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2016; 113(25): 6955-6960. Published 2016 Jun 06. doi: 10.1073/pnas.1513616113.

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Publication Date: 2016-06-06

Description: Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of KrasLA1/+;P53R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial–mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial–mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.

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Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria (2018)

Strangward, Patrick ; Haley, Michael J. ; Albornoz, Manuel G. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(28): 7404-7409. Published 2018 Jun 28. doi: 10.1073/pnas.1801737115.

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Publication Date: 2018-06-28

Description: Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1β production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1β release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33–NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.

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Constraints on the evolution of a doublesex target gene arising from doublesex’s pleiotropic deployment (2015)

Luo, Shengzhan D. ; Baker, Bruce S.

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(8): E852-E861. Published 2015 Feb 09. doi: 10.1073/pnas.1501192112.

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Publication Date: 2015-02-09

Description: “Regulatory evolution,” that is, changes in a gene’s expression pattern through changes at its regulatory sequence, rather than changes at the coding sequence of the gene or changes of the upstream transcription factors, has been increasingly recognized as a pervasive evolution mechanism. Many somatic sexually dimorphic features of Drosophila melanogaster are the results of gene expression regulated by the doublesex (dsx) gene, which encodes sex-specific transcription factors (DSXF in females and DSXM in males). Rapid changes in such sexually dimorphic features are likely a result of changes at the regulatory sequence of the target genes. We focused on the Flavin-containing monooxygenase-2 (Fmo-2) gene, a likely direct dsx target, to elucidate how sexually dimorphic expression and its evolution are brought about. We found that dsx is deployed to regulate the Fmo-2 transcription both in the midgut and in fat body cells of the spermatheca (a female-specific tissue), through a canonical DSX-binding site in the Fmo-2 regulatory sequence. In the melanogaster group, Fmo-2 transcription in the midgut has evolved rapidly, in contrast to the conserved spermathecal transcription. We identified two cis-regulatory modules (CRM-p and CRM-d) that direct sexually monomorphic or dimorphic Fmo-2 transcription, respectively, in the midguts of these species. Changes of Fmo-2 transcription in the midgut from sexually dimorphic to sexually monomorphic in some species are caused by the loss of CRM-d function, but not the loss of the canonical DSX-binding site. Thus, conferring transcriptional regulation on a CRM level allows the regulation to evolve rapidly in one tissue while evading evolutionary constraints posed by other tissues.

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Vacuolar ATPase depletion affects mitochondrial ATPase function, kinetoplast dependency, and drug sensitivity in trypanosomes (2015)

Baker, Nicola ; Hamilton, Graham ; Wilkes, Jonathan M. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(29): 9112-9117. Published 2015 Jul 06. doi: 10.1073/pnas.1505411112.

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Publication Date: 2015-07-06

Description: Kinetoplastid parasites cause lethal diseases in humans and animals. The kinetoplast itself contains the mitochondrial genome, comprising a huge, complex DNA network that is also an important drug target. Isometamidium, for example, is a key veterinary drug that accumulates in the kinetoplast in African trypanosomes. Kinetoplast independence and isometamidium resistance are observed where certain mutations in the F1-γ-subunit of the two-sector F1Fo-ATP synthase allow for Fo-independent generation of a mitochondrial membrane potential. To further explore kinetoplast biology and drug resistance, we screened a genome-scale RNA interference library in African trypanosomes for isometamidium resistance mechanisms. Our screen identified 14 V-ATPase subunits and all 4 adaptin-3 subunits, implicating acidic compartment defects in resistance; V-ATPase acidifies lysosomes and related organelles, whereas adaptin-3 is responsible for trafficking among these organelles. Independent strains with depleted V-ATPase or adaptin-3 subunits were isometamidium resistant, and chemical inhibition of the V-ATPase phenocopied this effect. While drug accumulation in the kinetoplast continued after V-ATPase subunit depletion, acriflavine-induced kinetoplast loss was specifically tolerated in these cells and in cells depleted for adaptin-3 or endoplasmic reticulum membrane complex subunits, also identified in our screen. Consistent with kinetoplast dispensability, V-ATPase defective cells were oligomycin resistant, suggesting ATP synthase uncoupling and bypass of the normal Fo-A6-subunit requirement; this subunit is the only kinetoplast-encoded product ultimately required for viability in bloodstream-form trypanosomes. Thus, we describe 30 genes and 3 protein complexes associated with kinetoplast-dependent growth. Mutations affecting these genes could explain natural cases of dyskinetoplasty and multidrug resistance. Our results also reveal potentially conserved communication between the compartmentalized two-sector rotary ATPases.

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Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity (2017)

Snarr, Brendan D. ; Baker, Perrin ; Bamford, Natalie C. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2017; 114(27): 7124-7129. Published 2017 Jun 20. doi: 10.1073/pnas.1702798114.

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Publication Date: 2017-06-20

Description: Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens Aspergillus fumigatus and Pseudomonas aeruginosa, respectively. These exopolysaccharides both contain 1,4-linked N-acetyl-d-galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3h from A. fumigatus and PelAh from P. aeruginosa) were found to degrade their respective polysaccharides in vitro. We therefore hypothesized that these glycoside hydrolases could exhibit antibiofilm activity and, further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment of A. fumigatus with Sph3h disrupted A. fumigatus biofilms with an EC50 of 0.4 nM. PelAh treatment also disrupted preformed A. fumigatus biofilms with EC50 values similar to those obtained for Sph3h. In contrast, Sph3h was unable to disrupt P. aeruginosa Pel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment of A. fumigatus hyphae with either Sph3h or PelAh significantly enhanced the activity of the antifungals posaconazole, amphotericin B, and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were noncytotoxic and protected A549 pulmonary epithelial cells from A. fumigatus-induced cell damage for up to 24 h. Intratracheal administration of Sph3h was well tolerated and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence.

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Fundamental insights into ontogenetic growth from theory and fish (2015)

Sibly, Richard M. ; Baker, Joanna ; Grady, John M. ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(45): 13934-13939. Published 2015 Oct 27. doi: 10.1073/pnas.1518823112.

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Publication Date: 2015-10-27

Description: The fundamental features of growth may be universal, because growth trajectories of most animals are very similar, but a unified mechanistic theory of growth remains elusive. Still needed is a synthetic explanation for how and why growth rates vary as body size changes, both within individuals over their ontogeny and between populations and species over their evolution. Here, we use Bertalanffy growth equations to characterize growth of ray-finned fishes in terms of two parameters, the growth rate coefficient, K, and final body mass, m∞. We derive two alternative empirically testable hypotheses and test them by analyzing data from FishBase. Across 576 species, which vary in size at maturity by almost nine orders of magnitude, K scaled as m∞−0.23. This supports our first hypothesis that growth rate scales as m∞−0.25 as predicted by metabolic scaling theory; it implies that species that grow to larger mature sizes grow faster as juveniles. Within fish species, however, K scaled as m∞−0.35. This supports our second hypothesis, which predicts that growth rate scales as m∞−0.33 when all juveniles grow at the same rate. The unexpected disparity between across- and within-species scaling challenges existing theoretical interpretations. We suggest that the similar ontogenetic programs of closely related populations constrain growth to m∞−0.33 scaling, but as species diverge over evolutionary time they evolve the near-optimal m∞−0.25 scaling predicted by metabolic scaling theory. Our findings have important practical implications because fish supply essential protein in human diets, and sustainable yields from wild harvests and aquaculture depend on growth rates.

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Hsp90 activator Aha1 drives production of pathological tau aggregates (2017)

Shelton, Lindsey B. ; Baker, Jeremy D. ; Zheng, Dali ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2017; 114(36): 9707-9712. Published 2017 Aug 21. doi: 10.1073/pnas.1707039114.

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Publication Date: 2017-08-21

Description: The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer’s disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood–brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

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Confirmation of intersubunit connectivity and topology of designed protein complexes by native MS (2018)

Sahasrabuddhe, Aniruddha ; Hsia, Yang ; Busch, Florian ; [et al.]

National Academy of Sciences

In: PNAS - Proceedings of the National Academy of Sciences of the United States of America. 2018; 115(6): 1268-1273. Published 2018 Jan 19. doi: 10.1073/pnas.1713646115.

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Publication Date: 2018-01-19

Description: Computational protein design provides the tools to expand the diversity of protein complexes beyond those found in nature. Understanding the rules that drive proteins to interact with each other enables the design of protein–protein interactions to generate specific protein assemblies. In this work, we designed protein–protein interfaces between dimers and trimers to generate dodecameric protein assemblies with dihedral point group symmetry. We subsequently analyzed the designed protein complexes by native MS. We show that the use of ion mobility MS in combination with surface-induced dissociation (SID) allows for the rapid determination of the stoichiometry and topology of designed complexes. The information collected along with the speed of data acquisition and processing make SID ion mobility MS well-suited to determine key structural features of designed protein complexes, thereby circumventing the requirement for more time- and sample-consuming structural biology approaches.

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