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Comprehensive Fitness Maps Of Hsp90 Show Widespread Environmental Dependence, Julia M. Flynn, Ammeret Rossouw, Pamela A. Cote-Hammarlof, Ines Fragata, David Mavor, Carl Hollins III, Claudia Bank, Daniel N. Bolon 2020 University of Massachusetts Medical School

Comprehensive Fitness Maps Of Hsp90 Show Widespread Environmental Dependence, Julia M. Flynn, Ammeret Rossouw, Pamela A. Cote-Hammarlof, Ines Fragata, David Mavor, Carl Hollins Iii, Claudia Bank, Daniel N. Bolon

Open Access Articles

Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard conditions and under five stress conditions. To our knowledge, these are the largest determined comprehensive fitness maps of point mutants. The growth of many variants differed between conditions, indicating that environment can have a large impact on Hsp90 evolution. Multiple variants provided growth advantages under individual conditions; however, these variants tended to exhibit ...


Dopamine Transporter Trafficking And Rit2 Gtpase: Mechanism Of Action And In Vivo Impact, Rita R. Fagan, Patrick Kearney, Carolyn G. Sweeney, Dino Luethi, Florianne E. Schoot Uiterkamp, Klaus Schicker, Brian S. Alejandro, Lauren C. O'Connor, Harald H. Sitte, Haley Melikian 2020 University of Massachusetts Medical School

Dopamine Transporter Trafficking And Rit2 Gtpase: Mechanism Of Action And In Vivo Impact, Rita R. Fagan, Patrick Kearney, Carolyn G. Sweeney, Dino Luethi, Florianne E. Schoot Uiterkamp, Klaus Schicker, Brian S. Alejandro, Lauren C. O'Connor, Harald H. Sitte, Haley Melikian

Open Access Articles

Following its evoked release, DA signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DAT. DAT surface availability is dynamically regulated by endocytic trafficking, and direct PKC activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals, or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 ...


Does Dna Methylation Matter In Fshd, Valentina Salsi, Frederique Magdinier, Rossella Ginevra Tupler 2020 University of Modena and Reggio Emilia

Does Dna Methylation Matter In Fshd, Valentina Salsi, Frederique Magdinier, Rossella Ginevra Tupler

Open Access Articles

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 ...


Targeting Trna-Synthetase Interactions Towards Novel Therapeutic Discovery Against Eukaryotic Pathogens, Paul Kelly, Fatemeh Hadi-Nezhad, Dennis Y. Liu, Travis J. Lawrence, Roger G. Linington, Michael Ibba, David H. Ardell 2020 The Ohio State University

Targeting Trna-Synthetase Interactions Towards Novel Therapeutic Discovery Against Eukaryotic Pathogens, Paul Kelly, Fatemeh Hadi-Nezhad, Dennis Y. Liu, Travis J. Lawrence, Roger G. Linington, Michael Ibba, David H. Ardell

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including ...


Peptidylarginine Deiminase Isozyme-Specific Pad2, Pad3 And Pad4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures And Cell Invasion In Two Glioblastoma Multiforme Cell Lines, Pinar Uysal-Onganer, Amy MacLatchy, Rayan Mahmoud, Igor Kraev, Paul R. Thompson, Jameel M. Inal, Sigrun Lange 2020 University of Westminster

Peptidylarginine Deiminase Isozyme-Specific Pad2, Pad3 And Pad4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures And Cell Invasion In Two Glioblastoma Multiforme Cell Lines, Pinar Uysal-Onganer, Amy Maclatchy, Rayan Mahmoud, Igor Kraev, Paul R. Thompson, Jameel M. Inal, Sigrun Lange

Open Access Articles

Glioblastoma multiforme (GBM) is an aggressive adult brain tumour with poor prognosis. Roles for peptidylarginine deiminases (PADs) in GBM have recently been highlighted. Here, two GBM cell lines were treated with PAD2, PAD3 and PAD4 isozyme-specific inhibitors. Effects were assessed on extracellular vesicle (EV) signatures, including EV-microRNA cargo (miR21, miR126 and miR210), and on changes in cellular protein expression relevant for mitochondrial housekeeping (prohibitin (PHB)) and cancer progression (stromal interaction molecule 1 (STIM-1) and moesin), as well as assessing cell invasion. Overall, GBM cell-line specific differences for the three PAD isozyme-specific inhibitors were observed on modulation of EV-signatures, PHB, STIM-1 ...


Stride-A Fluorescence Method For Direct, Specific In Situ Detection Of Individual Single- Or Double-Strand Dna Breaks In Fixed Cells, Magdalena M. Kordon, Miroslaw Zarebski, Kamil Solarczyk, Hanhui Ma, Thoru Pederson, Jurek W. Dobrucki 2020 Jagiellonian University

Stride-A Fluorescence Method For Direct, Specific In Situ Detection Of Individual Single- Or Double-Strand Dna Breaks In Fixed Cells, Magdalena M. Kordon, Miroslaw Zarebski, Kamil Solarczyk, Hanhui Ma, Thoru Pederson, Jurek W. Dobrucki

Open Access Articles

We here describe a technique termed STRIDE (SensiTive Recognition of Individual DNA Ends), which enables highly sensitive, specific, direct in situ detection of single- or double-strand DNA breaks (sSTRIDE or dSTRIDE), in nuclei of single cells, using fluorescence microscopy. The sensitivity of STRIDE was tested using a specially developed CRISPR/Cas9 DNA damage induction system, capable of inducing small clusters or individual single- or double-strand breaks. STRIDE exhibits significantly higher sensitivity and specificity of detection of DNA breaks than the commonly used terminal deoxynucleotidyl transferase dUTP nick-end labeling assay or methods based on monitoring of recruitment of repair proteins or ...


Proteomic And Transcriptional Profiles Of Human Stem Cell-Derived Beta Cells Following Enteroviral Challenge, Julius O. Nyalwidhe, Agata Jurczyk, Basanthi Satish, Sambra D. Redick, Natasha Qaisar, Melanie I. Trombly, Pranitha Vangala, Riccardo Racicot, Rita Bortell, David M. Harlan, Dale L. Greiner, Michael A. Brehm, Jerry L. Nadler, Jennifer P. Wang 2020 Eastern Virginia Medical School

Proteomic And Transcriptional Profiles Of Human Stem Cell-Derived Beta Cells Following Enteroviral Challenge, Julius O. Nyalwidhe, Agata Jurczyk, Basanthi Satish, Sambra D. Redick, Natasha Qaisar, Melanie I. Trombly, Pranitha Vangala, Riccardo Racicot, Rita Bortell, David M. Harlan, Dale L. Greiner, Michael A. Brehm, Jerry L. Nadler, Jennifer P. Wang

Open Access Articles

Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant beta-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived beta (SC-beta) cells are insulin-producing cell clusters that closely resemble native beta cells. To better understand the events precipitated by enteroviral infection of beta cells, we investigated transcriptional and proteomic changes in SC-beta cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-beta cells by immunostaining. Transcriptome analysis showed a decrease in insulin gene expression following ...


Neonatal-Derived Il-17 Producing Dermal Gammadelta T Cells Are Required To Prevent Spontaneous Atopic Dermatitis, Nicholas A. Spidale, Nidhi Malhotra, Michela Frascoli, Katelyn E. Sylvia, Bing Miu, Coral Freeman, Brian D. Stadinski, Eric Huseby, Joonso Kang 2020 University of Massachusetts Medical School

Neonatal-Derived Il-17 Producing Dermal Gammadelta T Cells Are Required To Prevent Spontaneous Atopic Dermatitis, Nicholas A. Spidale, Nidhi Malhotra, Michela Frascoli, Katelyn E. Sylvia, Bing Miu, Coral Freeman, Brian D. Stadinski, Eric Huseby, Joonso Kang

Open Access Articles

Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing gammadelta T (Tgammadelta17) cells, from birth resulted in spontaneous, highly penetrant AD with many of the major hallmarks of human AD. In Tgammadelta17 cell-deficient mice, basal keratinocyte transcriptome was altered months in advance ...


Cytosine Methylation Dynamics During Post-Testicular Sperm Maturation In Mammals [Preprint], Carolina Galan, Ryan W. Serra, Fengyun Sun, Vera Rinaldi, Colin C. Conine, Oliver J. Rando 2020 University of Massachusetts Medical School

Cytosine Methylation Dynamics During Post-Testicular Sperm Maturation In Mammals [Preprint], Carolina Galan, Ryan W. Serra, Fengyun Sun, Vera Rinaldi, Colin C. Conine, Oliver J. Rando

University of Massachusetts Medical School Faculty Publications

Beyond the haploid genome, mammalian sperm contribute a payload of epigenetic information which can modulate offspring phenotypes. Recent studies have shown that the small RNA payload of sperm undergoes extensive remodeling during post-testicular maturation in the epididymis. Intriguingly, epididymal maturation has also been linked to changes in the sperm methylome, suggesting that the epididymis might play a broader role in remodeling the sperm epigenome. Here, we build on prior studies of the maturing sperm methylation landscape, further characterizing the genome-wide methylation landscape in seven germ cell populations collected from throughout the male reproductive tract. Overall, we find very few changes ...


Ncapg Dynamically Coordinates The Myogenesis Of Fetal Bovine Tissue By Adjusting Chromatin Accessibility, Xin Hu, Yishen Xing, Xing Fu, Qiyuan Yang, Ling Ren, Yahui Wang, Qian Li, Junya Li, Lupei Zhang 2020 University of Li├Ęge

Ncapg Dynamically Coordinates The Myogenesis Of Fetal Bovine Tissue By Adjusting Chromatin Accessibility, Xin Hu, Yishen Xing, Xing Fu, Qiyuan Yang, Ling Ren, Yahui Wang, Qian Li, Junya Li, Lupei Zhang

Open Access Articles

NCAPG is a subunit of condensin I that plays a crucial role in chromatin condensation during mitosis. NCAPG has been demonstrated to be associated with farm animal growth traits. However, its role in regulating myoblast differentiation is still unclear. We used myoblasts derived from fetal bovine tissue as an in vitro model and found that NCAPG was expressed during myogenic differentiation in the cytoplasm and nucleus. Silencing NCAPG prolonged the mitosis and impaired the differentiation due to increased myoblast apoptosis. After 1.5 days of differentiation, silencing NCAPG enhanced muscle-specific gene expression. An assay for transposase-accessible chromatin- high throughput sequencing ...


Regulation Of Adipose Tissue Inflammation By Interleukin 6, Myoung Souk Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis 2020 University of Massachusetts Medical School

Regulation Of Adipose Tissue Inflammation By Interleukin 6, Myoung Souk Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis

Open Access Articles

Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These ...


Conformational Changes In The Ebola Virus Membrane Fusion Machine Induced By Ph, Ca2+, And Receptor Binding, Dibyendu Kumar Das, Uriel Bulow, William E. Diehl, Natasha D. Durham, Fernando Senjobe, Kartik Chandran, Jeremy Luban, James B. Munro 2020 Tufts University

Conformational Changes In The Ebola Virus Membrane Fusion Machine Induced By Ph, Ca2+, And Receptor Binding, Dibyendu Kumar Das, Uriel Bulow, William E. Diehl, Natasha D. Durham, Fernando Senjobe, Kartik Chandran, Jeremy Luban, James B. Munro

Open Access Articles

The Ebola virus (EBOV) envelope glycoprotein (GP) is a membrane fusion machine required for virus entry into cells. Following endocytosis of EBOV, the GP1 domain is cleaved by cellular cathepsins in acidic endosomes, removing the glycan cap and exposing a binding site for the Niemann-Pick C1 (NPC1) receptor. NPC1 binding to cleaved GP1 is required for entry. How this interaction translates to GP2 domain-mediated fusion of viral and endosomal membranes is not known. Here, using a bulk fluorescence dequenching assay and single-molecule Forster resonance energy transfer (smFRET)-imaging, we found that acidic pH, Ca2+, and NPC1 binding synergistically induce conformational ...


Analysis Of Oxidatively Damaged Proteins By Mass Spectrometry, Vincent Saullo 2020 The University of Western Ontario

Analysis Of Oxidatively Damaged Proteins By Mass Spectrometry, Vincent Saullo

Electronic Thesis and Dissertation Repository

As humans age, exposure to oxidative stress may induce protein degradation or aggregation; both resulting in loss of protein function. Protein oxidative damage remains a dominant pathology in many common ailments. To combat these pathologies, scientists must understand the nature of oxidative modifications and their effects on protein structure and dynamics. This work employs a range of mass spectrometry (MS) methods to characterize and analyze the effects of oxidative damage on the model protein myoglobin (Mb). Mb was oxidized using tert-butyl hydroperoxide, and the resulting modifications were characterized by top-down and bottom-up MS workflows. Hydrogen/deuterium exchange MS indicated elevated ...


Transcriptomics Of Gabra4 Knockout Mice Reveals Common Nmdar Pathways Underlying Autism, Memory, And Epilepsy, Cuixia Fan, Yue Gao, Guanmei Liang, Lang Huang, Jing Wang, Xiaoxue Yang, Yiwu Shi, Ursula C. Drager, Mei Zhong, Tian-Ming Gao, Xinping Yang 2020 Southern Medical University

Transcriptomics Of Gabra4 Knockout Mice Reveals Common Nmdar Pathways Underlying Autism, Memory, And Epilepsy, Cuixia Fan, Yue Gao, Guanmei Liang, Lang Huang, Jing Wang, Xiaoxue Yang, Yiwu Shi, Ursula C. Drager, Mei Zhong, Tian-Ming Gao, Xinping Yang

Open Access Articles

Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation ...


Skp, Cullin, F-Box (Scf)-Met30 And Scf-Cdc4-Mediated Proteolysis Of Cenp-A Prevents Mislocalization Of Cenp-A For Chromosomal Stability In Budding Yeast, Wei-Chun Au, Richard E. Baker, Munira A. Basrai 2020 National Institutes of Health

Skp, Cullin, F-Box (Scf)-Met30 And Scf-Cdc4-Mediated Proteolysis Of Cenp-A Prevents Mislocalization Of Cenp-A For Chromosomal Stability In Budding Yeast, Wei-Chun Au, Richard E. Baker, Munira A. Basrai

Open Access Articles

Restricting the localization of the histone H3 variant CENP-A (Cse4 in yeast, CID in flies) to centromeres is essential for faithful chromosome segregation. Mislocalization of CENP-A leads to chromosomal instability (CIN) in yeast, fly and human cells. Overexpression and mislocalization of CENP-A has been observed in many cancers and this correlates with increased invasiveness and poor prognosis. Yet genes that regulate CENP-A levels and localization under physiological conditions have not been defined. In this study we used a genome-wide genetic screen to identify essential genes required for Cse4 homeostasis to prevent its mislocalization for chromosomal stability. We show that two ...


A Thermophilic Phage Uses A Small Terminase Protein With A Fixed Helix-Turn-Helix Geometry, Janelle A. Hayes, Brendan J. Hilbert, Christl Gaubitz, Nicholas P. Stone, Brian A. Kelch 2020 University of Massachusetts Medical School

A Thermophilic Phage Uses A Small Terminase Protein With A Fixed Helix-Turn-Helix Geometry, Janelle A. Hayes, Brendan J. Hilbert, Christl Gaubitz, Nicholas P. Stone, Brian A. Kelch

Open Access Articles

Tailed bacteriophages use a DNA-packaging motor to encapsulate their genome during viral particle assembly. The small terminase (TerS) component of this DNA-packaging machinery acts as a molecular matchmaker that recognizes both the viral genome and the main motor component, the large terminase (TerL). However, how TerS binds DNA and the TerL protein remains unclear. Here, we identified gp83 of the thermophilic bacteriophage P74-26 as the TerS protein. We found that TerS(P76-26) oligomerizes into a nonamer that binds DNA, stimulates TerL ATPase activity, and inhibits TerL nuclease activity. A cryo-EM structure of TerS(P76-26) revealed that it forms a ring ...


Essential Role Of The Crk Family-Dosage In Digeorge-Like Anomaly And Metabolic Homeostasis, Akira Imamoto, Sewon Ki, Leiming Li, Kazunari Iwamoto, Venkat Maruthamuthu, John Devany, Ocean Lu, Suxiang Zhang, Takuji Yamada, Akiyoshi Hirayama, Shinji Fukuda, Yutaka Suzuki, Mariko Okada 2020 Old Dominion University

Essential Role Of The Crk Family-Dosage In Digeorge-Like Anomaly And Metabolic Homeostasis, Akira Imamoto, Sewon Ki, Leiming Li, Kazunari Iwamoto, Venkat Maruthamuthu, John Devany, Ocean Lu, Suxiang Zhang, Takuji Yamada, Akiyoshi Hirayama, Shinji Fukuda, Yutaka Suzuki, Mariko Okada

Mechanical & Aerospace Engineering Faculty Publications

CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal ...


Demarcation Of Sepsis-Induced Peripheral And Central Acidosis With Ph (Low) Insertion Cycle Peptide, Kelly E. Henry, Aisling M. Chaney, Veronica L. Nagle, Haley C. Cropper, Saghar Mozaffari, Chip Slaybaugh, Keykavous Parang, Oleg A. Andreev, Yana K. Reshetnyak, Michelle L. James, Jason S. Lewis 2020 Memorial Sloan Kettering Cancer Center

Demarcation Of Sepsis-Induced Peripheral And Central Acidosis With Ph (Low) Insertion Cycle Peptide, Kelly E. Henry, Aisling M. Chaney, Veronica L. Nagle, Haley C. Cropper, Saghar Mozaffari, Chip Slaybaugh, Keykavous Parang, Oleg A. Andreev, Yana K. Reshetnyak, Michelle L. James, Jason S. Lewis

Pharmacy Faculty Articles and Research

Acidosis is a key driver for many diseases, including cancer, sepsis, and stroke. The spatiotemporal dynamics of dysregulated pH across disease remain elusive, and current diagnostic strategies do not provide localization of pH alterations. We sought to explore if PET imaging using hydrophobic cyclic peptides that partition into the cellular membrane at low extracellular pH (denoted as pH [low] insertion cycles, or pHLIC) can permit accurate in vivo visualization of acidosis. Methods: Acid-sensitive cyclic peptide c[E4W5C] pHLIC was conjugated to bifunctional maleimide-NO2A and radiolabeled with 64Cu (half-life, 12.7 h). C57BL/6J mice were ...


Ck2-Dependent Phosphorylation Of The Brg1 Chromatin Remodeling Enzyme Occurs During Mitosis, Teresita Padilla-Benavides, Dominic T. Haokip, Yeonsoo Yoon, Pablo Reyes-Gutierrez, Jaime A. Rivera, Anthony N. Imbalzano 2020 University of Massachusetts Medical School

Ck2-Dependent Phosphorylation Of The Brg1 Chromatin Remodeling Enzyme Occurs During Mitosis, Teresita Padilla-Benavides, Dominic T. Haokip, Yeonsoo Yoon, Pablo Reyes-Gutierrez, Jaime A. Rivera, Anthony N. Imbalzano

Open Access Articles

Brg1 (Brahma-related gene 1) is one of two mutually exclusive ATPases that can act as the catalytic subunit of mammalian SWI/SNF (mSWI/SfigureNF) chromatin remodeling enzymes that facilitate utilization of the DNA in eukaryotic cells. Brg1 is a phospho-protein, and its activity is regulated by specific kinases and phosphatases. Previously, we showed that Brg1 interacts with and is phosphorylated by casein kinase 2 (CK2) in a manner that regulates myoblast proliferation. Here, we use biochemical and cell and molecular biology approaches to demonstrate that the Brg1-CK2 interaction occurred during mitosis in embryonic mouse somites and in primary myoblasts derived ...


Mtorc2-Akt Signaling To Atp-Citrate Lyase Drives Brown Adipogenesis And De Novo Lipogenesis, Camila Martinez Calejman, S. Trefely, S. W. Entwisle, Amelia K. Luciano, Su Myung. Jung, Wen-Yu Hsiao, A. Torres, C. M. Hung, H. Li, N. W. Snyder, J. Villen, K. E. Wellen, David A. Guertin 2020 University of Massachusetts Medical School

Mtorc2-Akt Signaling To Atp-Citrate Lyase Drives Brown Adipogenesis And De Novo Lipogenesis, Camila Martinez Calejman, S. Trefely, S. W. Entwisle, Amelia K. Luciano, Su Myung. Jung, Wen-Yu Hsiao, A. Torres, C. M. Hung, H. Li, N. W. Snyder, J. Villen, K. E. Wellen, David A. Guertin

Open Access Articles

mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation ...


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