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A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome

Ankit Bhatta1, Maninjay Atianand2, Zhaozhao Jiang1

  • 1Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.

Journal of Immunology (Baltimore, Md. : 1950)
|December 15, 2019
PubMed

Insights

Researchers discovered a new mitochondrial micropeptide, Mm47, crucial for Nlrp3 inflammasome activation in innate immunity. This peptide, encoded by a long noncoding RNA, plays a key role in immune responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Short open reading frame (sORF)-encoded peptides are increasingly recognized for their roles in biological processes.
  • Long noncoding RNAs (lncRNAs) are being explored for their potential to encode functional peptides.
  • Innate immunity relies on complex signaling pathways, including inflammasomes, to detect and respond to pathogens.

Purpose of the Study:

  • To identify and characterize novel micropeptides involved in innate immunity.
  • To investigate the function of a micropeptide derived from lncRNA 1810058I24Rik in macrophages.
  • To determine the role of the identified micropeptide in inflammasome activation.

Main Methods:

  • Identification of lncRNA 1810058I24Rik in mouse macrophages.
  • In vitro translation assays to confirm peptide production.
  • Subcellular localization studies using microscopy and fractionation.
  • CRISPR-Cas9 gene deletion and small interfering RNA (siRNA) knockdown in primary macrophages.
  • Analysis of inflammasome activation (Nlrp3, Nlrc4, Aim2) and TLR4 responses.

Main Results:

  • A novel micropeptide, mitochondrial micropeptide-47 (Mm47), was identified and localized to mitochondria.
  • Mm47 is translated from lncRNA 1810058I24Rik, which is downregulated by inflammatory stimuli.
  • Deletion or knockdown of Mm47 impaired Nlrp3 inflammasome activation but did not affect TLR4, Nlrc4, or Aim2 inflammasome responses.

Conclusions:

  • A novel mitochondrial micropeptide, Mm47, is essential for Nlrp3 inflammasome activation.
  • This study highlights the functional significance of sORF-encoded peptides in innate immunity.
  • Mm47 represents a new target for understanding and potentially modulating immune responses.

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