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  <doc>
    <id>53354</id>
    <completedYear/>
    <publishedYear>2021</publishedYear>
    <thesisYearAccepted/>
    <language>eng</language>
    <pageFirst>1</pageFirst>
    <pageLast>45</pageLast>
    <pageNumber/>
    <edition/>
    <issue/>
    <volume>April</volume>
    <type>other</type>
    <publisherName>Cold Spring Harbor Laboratory</publisherName>
    <publisherPlace/>
    <creatingCorporation/>
    <contributingCorporation/>
    <belongsToBibliography>0</belongsToBibliography>
    <completedDate>--</completedDate>
    <publishedDate>--</publishedDate>
    <thesisDateAccepted>--</thesisDateAccepted>
    <title language="eng">TCAIM controls effector T cell generation by preventing Mitochondria-Endoplasmic Reticulum Contact Site-initiated Cholesterol Biosynthesis</title>
    <abstract language="eng">T cells need to adapt their cellular metabolism for effector cell differentiation. This relies on alterations in mitochondrial physiology. Which signals and molecules regulate those alterations remains unclear. We recently reported, that the mitochondrial protein TCAIM inhibits activation-induced changes in mitochondrial morphology and function and thus, CD effector T cell formation. Using conditional TCAIM knock-in (KI) and knockout (KO) mice, w now show that it also applies to CD8+ T cells and more importantly, delineate the molecular processes in mitochondria by which TCAIM controls effector cell differentiation. TCAIM KI resulted in reduced activation-induced HIF1α protein expression. Metabolomics and transcriptional data in combination with mathematical  flux modeling revealed an impaired induction of anabolic pathways, especially of the mevalonate pathway and cholesterol biosynthesis in TCAIM KI CD8+ T cells. Addition of cholesterol completely rescued HIF1α protein expression, activation and proliferation of TCAIM KI CD8+ T cells. At the molecular level, TCAIM delayed activation-induced mitochondria-ER contact (MERC) formation by binding to MERC promoting proteins such as RMD3 and VDAC2. In summary, we demonstrate that TCAIM suppresses effector cell differentiation by inhibiting MERC formation, which induce HIF1α-mediated increase in cellular metabolism and cholesterol biosynthesis.</abstract>
    <parentTitle language="eng">bioRxiv</parentTitle>
    <identifier type="doi">10.1101/2021.04.20.440500</identifier>
    <identifier type="url">https://www.biorxiv.org/content/10.1101/2021.04.20.440500v1</identifier>
    <identifier type="urn">urn:nbn:de:kobv:b43-533543</identifier>
    <enrichment key="opus.source">publish</enrichment>
    <enrichment key="opus.doi.autoCreate">false</enrichment>
    <enrichment key="opus.urn.autoCreate">true</enrichment>
    <licence>Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International</licence>
    <author>C. Iwert</author>
    <author>J. Stein</author>
    <author>C. Appelt</author>
    <author>K. Vogt</author>
    <author>R. J. Rainer</author>
    <author>K. Tummler</author>
    <author>K. Mühle</author>
    <author>K. Stanko</author>
    <author>J. Schumann</author>
    <author>D. Uebe</author>
    <author>K. Jürchott</author>
    <author>Jan Lisec</author>
    <author>K. Janek</author>
    <author>C. Gille</author>
    <author>K. Textoris-Taube</author>
    <author>S. Sai</author>
    <author>A. Petersen</author>
    <author>A. A. Kühl</author>
    <author>E. Klipp</author>
    <author>C. Meisel</author>
    <author>B. Sawitzki</author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Mass Spectroscopy</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Metabolomics</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>Cancer</value>
    </subject>
    <collection role="ddc" number="543">Analytische Chemie</collection>
    <collection role="institutes" number="">1 Analytische Chemie; Referenzmaterialien</collection>
    <collection role="institutes" number="">1.7 Organische Spuren- und Lebensmittelanalytik</collection>
    <collection role="themenfelder" number="">Chemie und Prozesstechnik</collection>
    <collection role="themenfelder" number="">Chemische Charakterisierung und Spurenanalytik</collection>
    <collection role="literaturgattung" number="">Verlagsliteratur</collection>
    <collection role="fulltextaccess" number="">Datei für die Öffentlichkeit verfügbar ("Open Access")</collection>
    <collection role="unnumberedseries" number="">Arbeitspapiere der BAM</collection>
    <thesisPublisher>Bundesanstalt für Materialforschung und -prüfung (BAM)</thesisPublisher>
    <file>https://opus4.kobv.de/opus4-bam/files/53354/Iwert2021_bioRxiv.pdf</file>
  </doc>
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