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Reevaluating the role of human mitochondrial uL18m in the cytosolic stress response

Nature Structural & Molecular Biology volume 28, pages 474–475 (2021)Cite this article

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Matters Arising to this article was published on 31 May 2021

The Original Article was published on 13 April 2015

arising from X. Zhang et al. Nature Structural & Molecular Biology https://doi.org/10.1038/nsmb.3010 (2015)

A variety of stresses, including heat shock, lead to changes in gene expression patterns in mammalian cells caused by a general shutdown and reprogramming of cytosolic translation. This translational reprograming allows stress-resistant synthesis of heat shock and other cytoprotective proteins. In their article, Zhang et al. describe a moonlighting role of MRPL18 (uL18m hereafter), a canonical protein of the mitochondrial ribosome, in cytosolic translation reprogramming following heat shock1. Specifically, the authors propose that heat shock induces de novo translation of an uL18m isoform from a downstream open reading frame (dORF) that lacks the mitochondrial targeting sequence. This isoform associates directly with the cytosolic ribosome and causes it to preferentially translate stress-responsive messenger RNAs, such as Hsp70. Several years after the original publication, these findings still draw attention because of their implications for basic mitochondrial processes and translational control mechanisms, but confirmatory observations have yet to be published. Despite our genuine effort to replicate and build on one of the key findings of Zhang et al., our data indicate that uL18m is not necessary for the translational upregulation of HSP70 following heat shock in human cells.

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Fig. 1: Depletion of uL18m does not affect HSP70 induction on heat shock.

Data availability

Uncropped images of the blots presented in the paper are available at https://doi.org/10.6084/m9.figshare.14378510.v1 (Fig. 1) and https://doi.org/10.6084/m9.figshare.14377337.v1 (Extended Data Fig. 1). Source data are provided with this paper.

References

  1. Zhang, X. et al. Translational control of the cytosolic stress response by mitochondrial ribosomal protein L18. Nat. Struct. Mol. Biol. 22, 404–410 (2015).

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Acknowledgements

This research was supported by NIH-R35 grant no. GM118141 (to A.B.) and Muscular Dystrophy Association research grant no. MDA-381828 (to A.B.).

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Authors and Affiliations

  1. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

    Austin Choi & Antoni Barrientos

  2. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    Antoni Barrientos

Authors
  1. Austin Choi
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  2. Antoni Barrientos
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Contributions

A.C. and A.B. conceived the study. A.C. performed most experiments, and A.B. performed quantitative PCR analyses. A.C. and A.B. wrote and edited the paper.

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Correspondence to Antoni Barrientos.

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The authors declare no competing interests.

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Peer review information Anke Sparmann was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Depletion of uL18m using an alternative siRNA construct does not affect HSP70 induction upon heat shock.

a, HeLa cells were treated for 72-hours with siRNA targeting uL18m (Invitrogen), or left untreated, followed by heat-shock and recovery for 0–6 hours as indicated. ‘C’ indicates control cells that did not receive heat shock. (Left) Immunoblot of whole-cell lysates with the indicated antibodies. β-ACTIN is used as loading control. (Right) Quantification of relative HSP70 abundance presented as interleaved scatter plot. n = 5 independent experiments. b, As a), but in U87 cells, with recovery after heat shock for 0–8 hours as indicated. n = 3 independent experiments. c, As a), after 14 hours of treatment with the siRNA. n = 3 independent experiments. d, As b) after 14 hours of treatment with the siRNA. n = 4 independent experiments. In all the graphs in this figure, data are presented as mean values ± S.D. Statistical analyses were performed using the two-sided Student’s t-test in the Prism-6 software. No significant difference in HSP70 abundance between si-uL18m and control conditions was detected for any time point set; p<0.05. White space between the western blots indicates cropping of the blots to remove an irrelevant sample, but all samples were run on same gel. Additional replicates and data behind the graphs are available as source data online. Uncropped images of the presented blots are available at https://doi.org/10.6084/m9.figshare.14377337.v1.

Source data

Supplementary information

Supplementary Information

Supplementary Fig. 1, Methods and References.

Reporting Summary

Source data

Source data Fig. 1

Uncropped/unprocessed blots.

Source data Fig. 1

Statistical source data for graphs (densitometry).

Source data Extended Data Fig. 1

Uncropped/unprocessed blots.

Source data Extended Data Fig. 1

Statistical source data for graphs (densitometry).

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Choi, A., Barrientos, A. Reevaluating the role of human mitochondrial uL18m in the cytosolic stress response. Nat Struct Mol Biol 28, 474–475 (2021). https://doi.org/10.1038/s41594-021-00599-1

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