HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells

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  • Haiyang Yu
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
  • Shan Lu
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
  • Kelsey Gasior
    Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Digvijay Singh
    Division of Biological Sciences, University of California, San Diego, San Diego, CA, USA.
  • Sonia Vazquez-Sanchez
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
  • Olga Tapia
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • Divek Toprani
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
  • Melinda S. Beccari
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
  • John R. Yates
    Departments of Molecular Medicine and Neurobiology, The Scripps Research Institute, La Jolla, CA, USA.
  • Sandrine Da Cruz
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
  • Jay M. Newby
    Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Alberta, Canada.
  • Miguel Lafarga
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • Amy S. Gladfelter
    Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Elizabeth Villa
    Division of Biological Sciences, University of California, San Diego, San Diego, CA, USA.
  • Don W. Cleveland
    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.

Description

<jats:title>The makings of anisosomes</jats:title> <jats:p> Phase separation of proteins within the cell can produce a liquid-inside-a-liquid phase resembling oil droplets in water. Yu <jats:italic>et al.</jats:italic> now report that an RNA-binding protein called TDP-43, in which mutation and aggregation are linked to amyotrophic lateral sclerosis and frontotemporal dementia, phase separates into complex droplets, which they named anisosomes. This process occurred when TDP-43 lost its ability to bind RNA through disease-causing mutation or posttranslational acetylation. Anisosomes have spherical shells of TDP-43 (with properties of a liquid crystal) surrounding centers of the protein chaperone HSP70. Chaperone activity was required to maintain liquidity. Anisosomes formed in neurons in vivo when proteasome activity was inhibited and were converted into aggregates when adenosine triphosphate (ATP) levels fell. </jats:p> <jats:p> <jats:italic>Science</jats:italic> , this issue p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" related-article-type="in-this-issue" xlink:href="10.1126/science.abb4309">eabb4309</jats:related-article> </jats:p>

Journal

  • Science

    Science 371 (6529), eabb4309-, 2021-02-05

    American Association for the Advancement of Science (AAAS)

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