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MCL1 alternative polyadenylation is essential for cell survival and mitochondria morphology

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Abstract

Alternative polyadenylation in the 3′ UTR (3′ UTR-APA) is a mode of gene expression regulation, fundamental for mRNA stability, translation and localization. In the immune system, it was shown that upon T cell activation, there is an increase in the relative expression of mRNA isoforms with short 3′ UTRs resulting from 3′ UTR-APA. However, the functional significance of 3′ UTR-APA remains largely unknown. Here, we studied the physiological function of 3′ UTR-APA in the regulation of Myeloid Cell Leukemia 1 (MCL1), an anti-apoptotic member of the Bcl-2 family essential for T cell survival. We found that T cells produce two MCL1 mRNA isoforms (pA1 and pA2) by 3′ UTR-APA. We show that upon T cell activation, there is an increase in both the shorter pA1 mRNA isoform and MCL1 protein levels. Moreover, the less efficiently translated pA2 isoform is downregulated by miR-17, which is also more expressed upon T cell activation. Therefore, by increasing the expression of the more efficiently translated pA1 mRNA isoform, which escapes regulation by miR-17, 3′ UTR-APA fine tunes MCL1 protein levels, critical for activated T cells’ survival. Furthermore, using CRISPR/Cas9-edited cells, we show that depletion of either pA1 or pA2 mRNA isoforms causes severe defects in mitochondria morphology, increases apoptosis and impacts cell proliferation. Collectively, our results show that MCL1 alternative polyadenylation has a key role in the regulation of MCL1 protein levels upon T cell activation and reveal an essential function for MCL1 3′ UTR-APA in cell viability and mitochondria dynamics.

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Availability of data and material

The workflow for mitochondrial morphology analysis as well as the training datasets used can be downloaded from: https://github.com/econdesousa/ImageAnalysis/tree/master/MitochondrialStats and the workflow for the cell segmentation performed for the 2D intensity measurements can be downloaded from: https://github.com/econdesousa/CellPoseSegPlusIntensityMeasurement. Additional data that support the findings of this work are available upon request.

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Acknowledgements

The authors acknowledge the support of the i3S Scientific Platforms: Advanced Light Microscopy and Bioimaging, members of national infrastructure PPBI (supported by POCI-01-0145-FEDER-022122), Translational Cytometry Scientific Platform and Genomics Platform. The authors would like to thank Serviço de Imunohemoterapia of Centro Hospitalar Universitário de São João (CHUSJ), Porto for kindly donating the buffy coats. We are very grateful to Eric J. Wagner (UTMB, Houston, USA) and Joel R. Neilson (Baylor College of Medicine, Houston, USA) for reagents and helpful discussions and Elsa Logarinho, Catarina Meireles, Emília Cardoso and Rita Santos (i3S, Porto, Portugal) for the useful discussions on cytometry data.

Funding

This work was funded by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020-Operational Program for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior, in the framework of the project Institute for Research and Innovation in Health Sciences (POCI-01–0145-FEDER-007274). This study was also supported by the “Cancer Research on Therapy Resistance: From Basic Mechanisms to Novel Targets”—NORTE-01–0145-FEDER-000051 project, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 952334, by FCT under the project EXPL/SAU-PUB/1073/2021 and by Programa Operacional Regional do Norte and co-funded by European Regional Development Fund under the project “The Porto Comprehensive Cancer Center” with the reference NORTE-01–0145-FEDER-072678—Consórcio PORTO.CCC—Porto Comprehensive Cancer Center. EC-S was supported by the project PPBI-POCI-01–0145-FEDER-022122 in the scope of Fundação para a Ciência e Tecnologia, National Roadmap of Research Infrastructures. IP-C is funded by a Junior Researcher contract (DL 57/2016/CP1355/CT0016).

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Author notes

  1. Ana Curinha

    Present address: Department of Molecular Biology and Genetics, John Hopkins University School of Medicine, Baltimore, MD, USA

  2. Beatriz C. Garcia and Ana Curinha contributed equally to this work.

Authors and Affiliations

  1. Gene Regulation, i3S, Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, Porto, Portugal

    Isabel Pereira-Castro, Beatriz C. Garcia & Alexandra Moreira

  2. Gene Regulation, IBMC, Instituto de Biologia Molecular E Celular, Universidade Do Porto, Porto, Portugal

    Isabel Pereira-Castro, Beatriz C. Garcia, Ana Curinha & Alexandra Moreira

  3. Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal

    Ana Neves-Costa & Luís F. Moita

  4. i3S, Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, Porto, Portugal

    Eduardo Conde-Sousa

  5. INEB, Instituto de Engenharia Biomédica, Universidade Do Porto, Porto, Portugal

    Eduardo Conde-Sousa

  6. ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal

    Alexandra Moreira

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Contributions

IP-C designed and performed the experiments, analyzed the data and wrote the manuscript; BCG contributed to the experiments with the CRIPR/Cas9 cell lines; AC contributed to the miRNA experiments; AN-C generated some of the lentivirus used in this work; EC-S analyzed the mitochondria microscopy images and develop the workflows for image analysis; LFM contributed with intellectual input and revised the manuscript; AM designed and supervised the project and wrote the manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Isabel Pereira-Castro or Alexandra Moreira.

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The isolation of immune cells from buffy coats of healthy blood donors was approved by the Centro Hospitalar Universitário São João Ethics Committee (protocol 90/19), after each donor informed consent collection.

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Pereira-Castro, I., Garcia, B.C., Curinha, A. et al. MCL1 alternative polyadenylation is essential for cell survival and mitochondria morphology. Cell. Mol. Life Sci. 79, 164 (2022). https://doi.org/10.1007/s00018-022-04172-x

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