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

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 A. Chao, Stefan Kempa, Stefan Hüttelmaier, Matthias Selbach and Markus Landthaler ()
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Ulrike Zinnall: Berlin Institute for Medical Systems Biology
Miha Milek: Berlin Institute for Medical Systems Biology
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
Markus Landthaler: Berlin Institute for Medical Systems Biology

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30322-7

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