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

Zinnall, Ulrike; Milek, Miha; Minia, Igor; Vieira-Vieira, Carlos H.; Müller, Simon; Mastrobuoni, Guido; Hazapis, Orsalia-Georgia; Giudice, Simone Del; Schwefel, David; Bley, Nadine; Voigt, Franka; Chao, Jeffrey A.; Kempa, Stefan; Hüttelmaier, Stefan; Selbach, Matthias; Landthaler, Markus

doi:10.1038/s41467-022-30322-7

Cited by 12 publications

(22 citation statements)

References 95 publications

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“…5A ). Given that kmt5b modifies the epigenome ( 61 ) and hdlbpa regulates translation of secreted proteins ( 62 ), this difference is not unexpected. Among the shared genes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5 ). More work is needed to understand how these activity patterns arise, as many risk genes, including hdlbpa ( 62 ), impact physiology through changes to protein expression or synaptic physiology rather than mRNA dysregulation. Although less traditional than targeting molecular differences, it may be necessary to consider the correction of emergent phenotypes, such as increased brain activity, in developing a common treatment.…”

Section: Discussionmentioning

confidence: 99%

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Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Capps,

Moyer,

Conklin

et al. 2024

Preprint

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Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa, defined by increased activity mainly in the diencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multi-modal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.

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“…5A ). Given that kmt5b modifies the epigenome ( 61 ) and hdlbpa regulates translation of secreted proteins ( 62 ), this difference is not unexpected. Among the shared genes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Capps,

Moyer,

Conklin

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Center lines of violin plots depict the median values. (C) Violin plot of nuclear mature, cytosolic and membrane half-lives with transcripts classified by encoded targeting signals (TS) as in (Zinnall et al , 2022). Classification from left to right: cytosol-localized transcripts with no TS (n = 6745), nuclear DNA-encoded mitochondrial proteins (n = 807 with 709 being cytosol-localized), transcripts with tail-anchored transmembrane proteins (n = 86), membrane-localized transcripts with no known TS (n = 560), transcripts encoding signal peptides (n = 303) or transmembrane helices (n = 926) or both (n = 52).…”

Section: Resultsmentioning

confidence: 99%

“…Cytosolic half-lives of cytosol-localized transcripts were centered around half an hour, revealing that cytosol-and membrane-localized mRNAs have similar cytoplasmic stability, suggesting that differences in protein expression between cytosol-and membrane-localized transcripts with similar mRNA levels derive from differences in translational efficiency (Voigt et al, 2017;Lashkevich & Dmitriev, 2021;Zinnall et al, 2022). An intriguing prospect for future inquiry revolves around the impact of translation on the subcellular localization of mRNA.…”

Section: Discussionmentioning

confidence: 99%

Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting

Steinbrecht,

Minia,

Milek

et al. 2024

Preprint

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Eukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated mRNAs from over 9000 genes. In addition, we estimated transcript elongation rates. Many matured mRNAs have long nuclear half-lives, indicating nuclear retention as the rate-limiting step in the flow of mRNAs. In contrast, mRNA transcripts coding for transcription factors show fast kinetic rates, and in particular short nuclear half-lives. Differentially localized mRNAs have distinct rate constant combinations, implying modular regulation. Membrane stability is high for membrane-localized mRNA and cytosolic stability is high for cytosol-localized mRNA. mRNAs encoding target signals for membranes have low cytosolic and high membrane halflives with minor differences between signals. Transcripts of nuclear-encoded mitochondrial proteins have long nuclear retention and cytoplasmic kinetics that do not reflect co-translational targeting. Our data and analyses provide a useful resource to study spatiotemporal gene expression regulation.

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“…PKM2 knockdown results in inefficient targeting of its target mRNAs to the ER, but not to a control ER-localized mRNA, which is not a PKM2 target [ 41 ]. Second, HDLBP/Vigilin was found to associate with more than 80% of ER-localized mRNAs in HEK293 cells via high-affinity multivalent interactions with the coding sequence, as opposed to the 3′ UTR [ 66 ].…”

Section: Endoplasmic Reticulum-associated Ribosomes Are Different Fro...mentioning

confidence: 99%

Specialized Ribosomes in Health and Disease

Miller

MacDonald

Kellogg

et al. 2023

IJMS

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Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, and occurs in response to environmental stimuli. Mounting evidence supports the existence of specialized ribosomes, or specific changes to the ribosome that regulate the translation of a specific group of transcripts. These alterations have been shown to affect the affinity of ribosomes for certain mRNAs or change the cotranslational folding of nascent polypeptides at the exit tunnel. The identification of specialized ribosomes requires evidence of the incorporation of different ribosomal proteins or of modifications to rRNA and/or protein that lead(s) to physiologically relevant changes in translation. In this review, we summarize ribosomal heterogeneity and specialization in mammals and discuss their relevance to several human diseases.

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

Cited by 12 publications

References 95 publications

Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting

Specialized Ribosomes in Health and Disease

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