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A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome

Ankit Bhatta, Maninjay Atianand, Zhaozhao Jiang, Juliet Crabtree, Juliana Blin and Katherine A. Fitzgerald
J Immunol December 13, 2019, ji1900791; DOI: https://doi.org/10.4049/jimmunol.1900791
Ankit Bhatta
*Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
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Maninjay Atianand
†Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261
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Zhaozhao Jiang
*Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
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Juliet Crabtree
*Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
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Juliana Blin
*Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
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Katherine A. Fitzgerald
*Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
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Key Points

  • Annotated lncRNA 1810058I24Rik encodes a conserved mitochondrial micropeptide.

  • Macrophages fail to activate the Nlrp3 inflammasome in the absence of Mm47.

  • Genetic deletion of Mm47 in macrophages affects only Nlrp3 and not Aim2 or Nlrc4.

Abstract

Functional peptides encoded by short open reading frames are emerging as important mediators of fundamental biological processes. In this study, we identified a micropeptide produced from a putative long noncoding RNA (lncRNAs) that is important in controlling innate immunity. By studying lncRNAs in mice macrophages, we identified lncRNA 1810058I24Rik, which was downregulated in both human and murine myeloid cells exposed to LPS as well as other TLR ligands and inflammatory cytokines. Analysis of lncRNA 1810058I24Rik subcellular localization revealed that this transcript was localized in the cytosol, prompting us to evaluate its coding potential. In vitro translation with 35S-labeled methionine resulted in translation of a 47 aa micropeptide. Microscopy and subcellular fractionation studies in macrophages demonstrated endogenous expression of this peptide on the mitochondrion. We thus named this gene mitochondrial micropeptide-47 (Mm47). Crispr–Cas9–mediated deletion of Mm47, as well as small interfering RNA studies in mice primary macrophages, showed that the transcriptional response downstream of TLR4 was intact in cells lacking Mm47. In contrast, Mm47-deficient or knockdown cells were compromised for Nlrp3 inflammasome responses. Activation of Nlrc4 or Aim2 inflammasomes were intact in cells lacking Mm47. This study therefore identifies, to our knowledge, a novel mitochondrial micropeptide Mm47 that is required for the activation of the Nlrp3 inflammasome. This work further highlights the functional activity of short open reading frame–encoded peptides and underscores their importance in innate immunity.

Footnotes

  • This work was supported by grants from the National Institutes of Health (AI067497 to K.A.F.) and a T32 Training Grant (T32 AI095213 to A.B.).

  • The online version of this article contains supplemental material.

  • Received July 11, 2019.
  • Accepted November 10, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome
Ankit Bhatta, Maninjay Atianand, Zhaozhao Jiang, Juliet Crabtree, Juliana Blin, Katherine A. Fitzgerald
The Journal of Immunology December 13, 2019, ji1900791; DOI: 10.4049/jimmunol.1900791

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A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome
Ankit Bhatta, Maninjay Atianand, Zhaozhao Jiang, Juliet Crabtree, Juliana Blin, Katherine A. Fitzgerald
The Journal of Immunology December 13, 2019, ji1900791; DOI: 10.4049/jimmunol.1900791
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