Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation during early hypoxia
- Inserm UMR 1048, France
- Inserm U1031, France
- Inserm UMR 1037, France
- Université Paul Sabatier, France
- Tohoku Universtiy, Japan
Abstract
Hypoxia, a major inducer of angiogenesis, triggers major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to bind RNA and to activate the FGF1 IRES in hypoxia while it tends to inhibit several IRESs in normoxia. VASH1 depletion has also a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process to trigger new vessel formation in ischemic heart.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Lentivector plasmid complete maps and sequences are available on Dryad.
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Data from: Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxiaDryad Digital Repository, doi:10.5061/dryad.2330r1b.
Article and author information
Author details
Anne-Catherine Prats
Funding
Region Midi-Pyrenees
- Anne-Catherine Prats
AFM-Téléthon
- Edith Renaud-Gabardos
- Anne-Catherine Prats
Association pour la Recherche sur le Cancer
- Anne-Catherine Prats
European Commission (REFBIO VEMT)
- Anne-Catherine Prats
Fondation Toulouse Cancer-Sante
- Barbara Garmy-Susini
Agence Nationale de la Recherche (ANR-18-CE11-0020-RIBOCARD)
- Anne-Catherine Prats
Ligue Contre le Cancer
- Fransky Hantelys
- Anne-Claire Godet
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Hantelys et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation during early hypoxia
eLife 8:e50094.
https://doi.org/10.7554/eLife.50094
Further reading
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- Cell Biology
Distal appendages are nine-fold symmetric blade-like structures attached to the distal end of the mother centriole. These structures are critical for formation of the primary cilium, by regulating at least four critical steps: ciliary vesicle recruitment, recruitment and initiation of intraflagellar transport (IFT), and removal of CP110. While specific proteins that localize to the distal appendages have been identified, how exactly each protein functions to achieve the multiple roles of the distal appendages is poorly understood. Here we comprehensively analyze known and newly discovered distal appendage proteins (CEP83, SCLT1, CEP164, TTBK2, FBF1, CEP89, KIZ, ANKRD26, PIDD1, LRRC45, NCS1, CEP15) for their precise localization, order of recruitment, and their roles in each step of cilia formation. Using CRISPR-Cas9 knockouts, we show that the order of the recruitment of the distal appendage proteins is highly interconnected and a more complex hierarchy. Our analysis highlights two protein modules, CEP83-SCLT1 and CEP164-TTBK2, as critical for structural assembly of distal appendages. Functional assays revealed that CEP89 selectively functions in RAB34+ ciliary vesicle recruitment, while deletion of the integral components, CEP83-SCLT1-CEP164-TTBK2, severely compromised all four steps of cilium formation. Collectively, our analyses provide a more comprehensive view of the organization and the function of the distal appendage, paving the way for molecular understanding of ciliary assembly.
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- Cell Biology
The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the cilium is initiated by recruitment of ciliary vesicles to the distal appendage of the mother centriole. However, the distal appendage mechanism that directly captures ciliary vesicles is yet to be identified. In an accompanying paper, we show that the distal appendage protein, CEP89, is important for the ciliary vesicle recruitment, but not for other steps of cilium formation (Tomoharu Kanie, Love, Fisher, Gustavsson, & Jackson, 2023). The lack of a membrane binding motif in CEP89 suggests that it may indirectly recruit ciliary vesicles via another binding partner. Here, we identify Neuronal Calcium Sensor-1 (NCS1) as a stoichiometric interactor of CEP89. NCS1 localizes to the position between CEP89 and a ciliary vesicle marker, RAB34, at the distal appendage. This localization was completely abolished in CEP89 knockouts, suggesting that CEP89 recruits NCS1 to the distal appendage. Similarly to CEP89 knockouts, ciliary vesicle recruitment as well as subsequent cilium formation was perturbed in NCS1 knockout cells. The ability of NCS1 to recruit the ciliary vesicle is dependent on its myristoylation motif and NCS1 knockout cells expressing a myristoylation defective mutant failed to rescue the vesicle recruitment defect despite localizing properly to the centriole. In sum, our analysis reveals the first known mechanism for how the distal appendage recruits the ciliary vesicles.
