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HDLBP binds ER-targeted mRNAs by multivalent interactions to promote protein synthesis of transmembrane and secreted proteins

Author

Listed:
  • Ulrike Zinnall

    (Berlin Institute for Medical Systems Biology)

  • Miha Milek

    (Berlin Institute for Medical Systems Biology
    National Institute of Chemistry
    Berlin Institute of Health at Charité)

  • Igor Minia

    (Berlin Institute for Medical Systems Biology)

  • Carlos H. Vieira-Vieira

    (Berlin Institute for Medical Systems Biology)

  • Simon Müller

    (Martin Luther University)

  • Guido Mastrobuoni

    (Berlin Institute for Medical Systems Biology)

  • Orsalia-Georgia Hazapis

    (Berlin Institute for Medical Systems Biology)

  • Simone Giudice

    (Berlin Institute for Medical Systems Biology)

  • David Schwefel

    (Charite-Universitätsmedizin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics)

  • Nadine Bley

    (Martin Luther University)

  • Franka Voigt

    (Friedrich Miescher Institute for Biomedical Research)

  • Jeffrey A. Chao

    (Friedrich Miescher Institute for Biomedical Research)

  • Stefan Kempa

    (Berlin Institute for Medical Systems Biology)

  • Stefan Hüttelmaier

    (Martin Luther University)

  • Matthias Selbach

    (Berlin Institute for Medical Systems Biology
    Charite-Universitätsmedizin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics)

  • Markus Landthaler

    (Berlin Institute for Medical Systems Biology
    Humboldt-Universität zu Berlin)

Abstract

The biological role of RNA-binding proteins in the secretory pathway is not well established. Here, we describe that human HDLBP/Vigilin directly interacts with more than 80% of ER-localized mRNAs. PAR-CLIP analysis reveals that these transcripts represent high affinity HDLBP substrates and are specifically bound in their coding sequences (CDS), in contrast to CDS/3’UTR-bound cytosolic mRNAs. HDLBP crosslinks strongly to long CU-rich motifs, which frequently reside in CDS of ER-localized mRNAs and result in high affinity multivalent interactions. In addition to HDLBP-ncRNA interactome, quantification of HDLBP-proximal proteome confirms association with components of the translational apparatus and the signal recognition particle. Absence of HDLBP results in decreased translation efficiency of HDLBP target mRNAs, impaired protein synthesis and secretion in model cell lines, as well as decreased tumor growth in a lung cancer mouse model. These results highlight a general function for HDLBP in the translation of ER-localized mRNAs and its relevance for tumor progression.

Suggested Citation

  • Ulrike Zinnall & Miha Milek & Igor Minia & Carlos H. Vieira-Vieira & Simon Müller & Guido Mastrobuoni & Orsalia-Georgia Hazapis & Simone Giudice & David Schwefel & Nadine Bley & Franka Voigt & Jeffrey, 2022. "HDLBP binds ER-targeted mRNAs by multivalent interactions to promote protein synthesis of transmembrane and secreted proteins," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30322-7
    DOI: 10.1038/s41467-022-30322-7
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    References listed on IDEAS

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