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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA present address:University of Colorado Boulder BoulderCO 80309USA present address:Dana Farber Cancer Institute BostonMA 02215USA present address:Massachusetts Institute of Technology BostonMA 02139USA present address:Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

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Exploring unconventional attributes of red blood cells and their potential applications in biomedicine

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Protein & Cell 2024年第5期15卷 315-330页

作者： Alkmini T.Anastasiadi Vasiliki-Zoi Arvaniti Krystalyn E.Hudson Anastasios G.Kriebardis Constantinos Stathopoulos Angelo D’Alessandro Steven L.Spitalnik Vassilis L.Tzounakas Department of Biochemistry School of MedicineUniversity of Patras26504 PatrasGreece Department of Pathology and Cell Biology Columbia University Irving Medical CenterNew York CityNY 10032USA Laboratory of Reliability and Quality Control in Laboratory Hematology(HemQcR) Department of Biomedical SciencesSchool of Health&Caring SciencesUniversity of West Attica(UniWA)12243 EgaleoGreece Department of Biochemistry and molecular genetics University of Colorado Anschutz Medical Campus13001 AuroraCOUSA present address:Institute for Fundamental Biomedical Research(IFBR) Biomedical Sciences Research Center“Alexander Fleming”Vari11527 AthensGreece

We need to talk about red blood cells.Eukaryotic cells are defined as cells containing distinct nuclei and other membranous organelles.However,red blood cells(RBCs)lack a nucleus and organelles—perhaps to limit the generation of reactive oxygen species(Zhang et al.,2011)—and are filled with hemoglobin(Hb).This oxygen carrier is limited to the cytosol by the cell membrane and cytoskeleton,which maintain cellular integrity and deformability as RBCs pass through narrow capillaries(Gratzer,1994)to perform their primary function of gas exchange.

关键词： al. membranous maintain

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Cellular and molecular Requirements for Polar PIN Targeting and Transcytosis in Plants

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molecular Plant 2008年第6期1卷 1056-1066页

作者： Jurgen Kleine-Vehn tukasz tangowski Justyna Wisniewska Pankaj Dhonukshe Philip B Brewer Jiri Friml Department of Plant Systems Biology VIB and Department of Molecular Genetics Ghent University 9052 Gent Belgium Zentrum fur Molekularbiologie der Pflanzen (ZMBP) Universitat Tubingen 72076 Tubingen Germany present address: Institute of General and molecular Biology Nicolas Copernicus University 87-100 Torun Poland present address: Department of Biology Utrecht University 3508 TB Utrecht The Netherlands present address: Centre for Integrative Legume Research University of Queensland Brisbane Australia

The polar, sub-cellular localization of PIN auxin efflux carriers determines the direction of intercellular auxin flow, thus defining the spatial aspect of auxin signalling. Dynamic, transcytosis-like relocalizations of PIN proteins occur in response to external and internal signals, integrating these signals into changes in auxin distribution. Here, we examine the cellular and molecular mechanisms of polar PIN delivery and transcytosis. The mechanisms of the ARF-GEF-dependent polar targeting and transcytosis are well conserved and show little variations among diverse Arabidopsis ecotypes consistent with their fundamental importance in regulating plant development. At the cellular level, we refine previous findings on the role of the actin cytoskeleton in apical and basal PIN targeting, and identify a previously unknown role for microtubules, specifically in basal targeting. PIN protein delivery to different sides of the cell is mediated by ARFdependent trafficking with a previously unknown complex level of distinct ARF-GEF vesicle trafficking regulators. Our data suggest that alternative recruitment of PIN proteins by these distinct pathways can account for cell type- and cargo-specific aspects of polar targeting, as well as for polarity changes in response to different signals. The resulting dynamic PIN positioning to different sides of cells defines a three-dimensional pattern of auxin fluxes within plant tissues.

关键词： cytoskeleton polarity protein targeting.

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Transcriptional, post-transcriptional and post-translational regulations of gene expression during leaf polarity formation

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Cell Research 2007年第6期17卷 512-519页

作者： Lin Xu Li YangHai Huang National Laboratory of Plant molecular genetics, Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Road, Shanghai 200032, China National Laboratory of Plant molecular genetics Shanghai Institute of Plant Physiology and Ecology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China present address: IBMP CNRS Universite Louis Pasteur 67084 Strasbourg France present address: Department of Biology University of Pennsylvania Philadelphia PA 19104 USA

Leaf morphogenesis requires the establishment of adaxial-abaxial polarity after primordium initiation from the shootapical meristem (SAM). Several families of transcription factors are known to play critical roles in promoting adaxial orabaxial leaf fate. Recently, post-transcriptional gene silencing pathways have been shown to regulate the establishmentof leaf polarity, providing novel and exciting insights into leaf development. For example, microRNAs (miR165/166)and a trans-acting siRNA (TAS3-derived tasiR-ARF) have been shown to repress the expression of several key transcrip-tion factor genes. In addition, yet another level of regulation, post-translational regulation, has been revealed recently bystudies on the role of the 26S proteasome in leaf polarity. Although our understanding regarding the molecular mecha-nisms underlying establishment of adaxial-abaxial polarity has greatly improved, there is still much that remains elusive.This review aims to discuss recent progress, as well as the remaining questions, regarding the molecular mechanismsunderlying leaf polarity formation.

关键词： Arabidopsis leaf development polarity formation

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Defective Etioplasts Observed in Variegation Mutants May Reveal the Light-Independent Regulation of White/Yellow Sectors of Arabidopsis Leaves

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Journal of Integrative Plant Biology 2011年第11期53卷 846-857页

作者： Wenjuan Wu Nabil Elsheery Qing Wei Lingang Zhang Jirong Huang National Key Laboratory of Plant molecular genetics Institute of Plant-PhysTology and-Ecology Shanghai Institutesfor Biological Sciences the Chinese Academy of Sciences Shanghai 200032 China present address： Division of Nephrology and Hypertension Mayo Clinic Rochester MN 55905 USA present address： Institute of Plant Science and Resources okayama University Kurashiki Okayama Japan

Leaf variegation resulting from nuclear gene mutations has been used as a model system to elucidate the molecular mechanisms of chloroplast development. Since most variegation genes also function in photosynthesis, it remains unknown whether their roles in photosynthesis and chloroplast development are distinct. Here, using the variegation mutant thylakoid formation1 （thfl） we show that variegation formation is light independent. It was found that slow and uneven chloroplast development in thfl can be attributed to defects in etioplast development in darkness. Ultrastructural analysis showed the coexistence of plastids with or without prolamellar bodies （PLB） in cells of thfl, but not of WT. Although THF1 mutation leads to significant decreases in the levels of Pchlide and Pchliide oxidoreductase （POR） expression, genetic and 5-aminolevulinic acid （ALA）-feeding analysis did not reveal Pchlide or POR to be critical factors for etioplast formation in thfl. Northern blot analysis showed that plastid gene expression is dramatically reduced in thfl compared with that in WT, particularly in the dark. Our results also indicate that chlorophyll biosynthesis and expression of plastidic genes are coordinately suppressed in thfl. Based on these results, we propose a model to explain leaf variegation formation from the plastid development perspective.

关键词： Arabidopsis chloroplast etioplast THF1/Psb29 variegation Pchllide oxidoreductase Pchlide oxidoreductase chloroplastdevelopment.

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Functional Analysis of Semi-conserved Transit Peptide Motifs and Mechanistic Implications in Precursor Targeting and Recognition

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molecular Plant 2016年第9期9卷 1286-1301页

作者： Kristen Holbrook Chitra Subramanian Prakitchai Chotewutmontri L. Evan Reddick Sarah Wright Huixia Zhang Lily Moncrief Barry D. Bruce Department of Biochemistry Cellular and Molecular Biology Graduate Program in Plant Physiology and genetics Graduate School of Genome Science and Technology Department of Botany Department of BotanyUniversity of Tennessee Knoxville TN 37996 USA present address: Department of Infectious Disease St. Jude Children's Research Hospital Memphis TN 38105 USA present address: Institute of molecular Biology University of Oregon Eugene OR 97403 USA present address: Department of Microbiology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas TX 75390 USA present address: Albert R. Mann Library Cornell University Ithaca NY 14850 USA present address: U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring MD 20993 USA

Over 95% of plastid proteins are nuclear-encoded as their precursors containing an N-terminal extension known as the transit peptide （TP）. Although highly variable, TPs direct the precursors through a conserved, posttranslational mechanism involving translocons in the outer （TOC） and inner envelope （TOC）. The organelle import specificity is mediated by one or more components of the Toc complex. However, the high TP diversity creates a paradox on how the sequences can be specifically recognized. An emerging model of TP design is that they contain multiple loosely conserved motifs that are recognized at different steps in the targeting and transport process. Bioinformatics has demonstrated that many TPs contain semiconserved physicochemical motifs, termed FGLK. In order to characterize FGLK motifs in TP recognition and import, we have analyzed two well-studied TPs from the precursor of RuBisCO small subunit （SStp） and ferredoxin （Fdtp）. Both SStp and Fdtp contain two FGLK motifs. Analysis of large set mutations （-85） in these two motifs using in vitro, in organello, and in vivo approaches support a model in which the FGLK domains mediate interaction with TOC34 and possibly other TOC components. In vivo import analysis suggests that multiple FGLK motifs are functionally redundant. Furthermore, we discuss how FGLK motifs are required for efficient precursor protein import and how these elements may permit a convergent function of this highly variable class of targeting sequences.

关键词： chloroplast biology protein translocation Toc34 transit peptide cell biology

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The boys are back in town: Rethinking the function of ribosomal DNA repeats in the genomic era

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molecular Plant 2023年第3期16卷 514-516页

作者： Francesca B.Lopez Peter C.McKeown Antoine Fort Galina Brychkova Charles Spillane genetics and Biotechnology Laboratory Plant&AgriBiosciences Research Centre(PABC)Ryan InstituteUniversity of GalwayH91 REW4 GalwayIreland present address:Department of Plant Biology and Genome Center University of CaliforniaDavisUC Davis Genome CenterDavisCA 95616USA

Next-generation sequencing technological advances,affording high-throughput,scalable,and fast assemblies,have enabled genome editing techniques that allow us to remove,insert,and modify genes for rapid and precise fun... 详细信息

关键词： remove precise function

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Britanin–a beacon of hope against gastrointestinal tumors?

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World Journal of Clinical Oncology 2024年第4期15卷 523-530页

作者： Agnieszka Kajdanek Damian Kołat Lin-Yong Zhao Mateusz Kciuk Zbigniew Pasieka Żaneta Kałuzińska-Kołat Department of Biomedicine and Experimental Surgery Medical University of LodzLodz 90-136LodzkiePoland Department of Functional Genomics Medical University of LodzLodz 90-752LodzkiePoland Department of General Surgery&Laboratory of Gastric Cancer State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina Gastric Cancer Center West China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina Department of molecular Biotechnology and genetics University of LodzLodz 90-237LodzkiePoland

Britanin is a bioactive sesquiterpene lactone known for its potent anti-inflammatory and anti-oxidant properties.It also exhibits significant anti-tumor activity,suppressing tumor growth in vitro and in vivo.The current body of research on Britanin includes thirty papers predominantly related to neoplasms,the majority of which are gastrointestinal tumors that have not been summarized before.To drive academic debate,the present paper reviews the available research on Britanin in gastrointestinal tumors.It also outlines novel research directions using data not directly concerned with the digestive system,but which could be adopted in future gastrointestinal research.Britanin was found to counteract liver,colorectal,pancreatic,and gastric tumors,by regulating proliferation,apoptosis,autophagy,immune response,migration,and angiogenesis.As confirmed in pancreatic,gastric,and liver cancer,its most commonly noted molecular effects include nuclear factor kappa B and B-cell lymphoma 2 downregulation,as well as Bcl-2-associated X protein upregulation.Moreover,it has been found to induce the Akt kinase and Forkhead box O1 axis,activate the AMP-activated protein kinase pathway,elevate interleukin-2 and peroxisome proliferator-activated receptor-γlevels,reduce interleukin-10,as well as downregulate matrix metalloproteinase-9,Twist family bHLH transcription factor 1,and cyclooxygenase-2.It also inhibits Myc–HIF1αinteraction and programmed death ligand 1 transcription by interrupting the Ras/RAF/MEK/ERK pathway and mTOR/P70S6K/4EBP1 signaling.Future research should aim to unravel the link between Britanin and acetylcholinesterase,mast cells,osteolysis,and ischemia,as compelling data have been provided by studies outside the gastrointestinal context.Since the cytotoxicity of Britanin on noncancerous cells is significantly lower than that on tumor cells,while still being effective against the latter,further in-depth studies with the use of animal models are merited.The compound exhibits pleiotropic biological activity and offers

关键词： Britanin Sesquiterpene lactones Chemotherapeutics Gastrointestinal tumors In vitro In vivo

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An INDEHISCENT-Controlled Auxin Response Specifies the Separation Layer in Early Arabidopsis Fruit

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molecular Plant 2016年第6期9卷 857-869页

作者： Kasper van Gelderen Martin van Rongen An'an Liu Anne Otten Remko Offringa molecular and DeveLopmental genetics Institute of Biology Leiden Leiden University Sylviusweg 72 2333 BE Leiden the Netherlands These authors contributed equally to this article. present address: Plant EcophysJology Institute of Environmental Biology Utrecht University 3584 CH Utrecht the Netherlands present address: Sainsbury Laboratory 47 Sateman Street Cambridge CB2 1LR UK

Seed dispersal is an important moment in the life cycle of a plant species. In Arabidopsis thaliana, it is dependent on transcription factor INDEHISCENT （IND）-mediated specification of a separation layer in the dehiscence zone found in the margin between the valves （carpel walls） and the central replum of the developing fruit. It was proposed that IND specifies the separation layer by inducing a local auxin minimum at late stages of fruit development. Here we show that morphological differences between the ind mutant and wild-type fruit already arise at early stages of fruit development, coinciding with strong IND expression in the valve margin. We show that IND-reduced PIN-FORMED3 （PIN3） auxin efflux carrier abundance leads to an increased auxin response in the valve margin during early fruit develop- ment, and that the concomitant cell divisions that form the dehiscence zone are lacking in ind mutant fruit. Moreover, IND promoter-driven ectopic expression of the AGC kinases PINOID （PID） and WAG2 induced indehiscence by expelling auxin from the valve margin at stages 14-16 of fruit development through increased PIN3 abundance. Our results show that IND, besides its role at late stages of Arabi- dopsis fruit development, functions at early stages to facilitate the auxin-triggered cell divisions that form the dehiscence zone.

关键词： seed dispersal polar auxin transport PINOID INDEHISCENT separation layer Arabidopsis

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Timing Is Everything： Highly Specific and Transient Expression of a MAP Kinase Determines Auxin-Induced Leaf Venation Patterns in Arabidopsis

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molecular Plant 2014年第11期7卷 1637-1652页

作者： Vera Stanko Concetta Giuliani Katarzyna Retzer Armin Djamei Vanessa Wahl Bernhard Wurzinger Cathal Wilson Erwin Heberle-Bors Markus Teige Friedrich Kragler Department of Plant molecular Biology Max. F. Perutz Laboratories University of Vienna Dr. Bohrgasse 9/4 Vienna A-1030 Austria present address: Felix-Klein-Gymnasium Bottingerstraβe 17 D-37073 Gottingen Germany present address: Austrian Centre of Industrial Biotechnology Muthgasse 11 A-1190 Vienna Austria present address: Department of Applied genetics and Cell Biology University of Natural Resources and Life Sciences Muthgasse 18 A-1190 Vienna Austria present address: Gregor Mendel Institute of molecular Plant Biology Dr. Bohr-Gasse 3 1030 Vienna Austria Max Planck Institute of molecular Plant Physiology Wissenschaftspark Golm Am Muhlenberg 1 D-14476 Potsdam-Golm Germany Department of Biochemistry Max. F. Perutz Laboratories University of Vienna Dr. Bohrgasse 9/5 Vienna A-1030 Austria present address: Department of Ecogenomics and Systems Biology University of Vienna Althanstr. 14 A-1090 Vienna Austria present address: Telethon Institute of genetics and Medicine Via Pietro Castellino 11180131-Naples Italy Department of Ecogenomics and Systems Biology University of Vienna AIthanstr. 14 A-1090 Vienna Austria

Mitogen-activated protein kinase （MAPK） cascades are universal signal transduction modules present in all eukaryotes. In plants, MAPK cascades were shown to regulate cell division, developmental processes, stress responses, and hormone pathways. The subgroup A of Arabidopsis MAPKs consists of AtMPK3, AtMPK6, and AtMPK10. AtMPK3 and AtMPK6 are activated by their upstream MAP kinase kinases （MKKs） AtMKK4 and AtMKK5 in response to biotic and abiotic stress. In addition, they were identified as key regulators of stomatal development and patterning. AtMPKIO has long been considered as a pseudo-gene, derived from a gene duplication of AtMPK6. Here we show that AtMPKIO is expressed highly but very transiently in seedlings and at sites of local auxin maxima leaves. MPK10 encodes a functional kinase and interacts with the upstream MAP kinase kinase （MAPKK） AtMKK2. mpklO mutants are delayed in flowering in long-day conditions and in continuous light. Moreover, cotyledons of mpk10 and mkk2 mutants have reduced vein complexity, which can be reversed by inhibiting polar auxin transport （PAT）. Auxin does not affect AtMPKIO expression while treatment with the PAT inhibitor HFCA extends the expression in leaves and reverses the mpklO mutant phenotype. These results suggest that the AtMKK2-AtMPK10 MAPK module regulates venation complexity by altering PAT efficiency.

关键词： Arabidopsis MAP kinase leaf development polar auxin transport leaf venation pattern.

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