Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity

• Published in: Nature communications Vol. 12; no. 1; p. 2130
• Main Authors: Lee, Cheryl Q. E., Kerouanton, Baptiste, Chothani, Sonia, Zhang, Shan, Chen, Ying, Mantri, Chinmay Kumar, Hock, Daniella Helena, Lim, Radiance, Nadkarni, Rhea, Huynh, Vinh Thang, Lim, Daryl, Chew, Wei Leong, Zhong, Franklin L., Stroud, David Arthur, Schafer, Sebastian, Tergaonkar, Vinay, St John, Ashley L., Rackham, Owen J. L., Ho, Lena
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-04-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/21; 13/31; 13/51; 14/19; 3' Untranslated regions; 38/91; 631/250/1933; 631/250/2502; 631/250/256/2516; 631/250/262; 82/58; 82/80; Antiviral agents; Cell Line; Cytochrome; Cytochrome-c oxidase; Cytochromes; Electron Transport Complex IV - genetics; Electron Transport Complex IV - metabolism; Gene Knockout Techniques; Genetic Pleiotropy - immunology; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunity; Infections; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Membrane potential; Membrane Potential, Mitochondrial - immunology; Metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mitochondria; Mitochondria - immunology; Mitochondria - pathology; multidisciplinary; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidase; Oxidative metabolism; Peptides; Primary Cell Culture; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Transcription; Up-Regulation - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22397-5

Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for mito-SEPs that modify inflammatory outcomes and report a mito-SEP named “Modulator of cytochrome C oxidase during Inflammation” (MOCCI) that is upregulated during inflammation and infection to promote host-protective resolution. MOCCI, a paralog of the NDUFA4 subunit of cytochrome C oxidase (Complex IV), replaces NDUFA4 in Complex IV during inflammation to lower mitochondrial membrane potential and reduce ROS production, leading to cyto-protection and dampened immune response. The
MOCCI
transcript also generates miR-147b, which targets the
NDUFA4
mRNA with similar immune dampening effects as MOCCI, but simultaneously enhances RIG-I/MDA-5-mediated viral immunity. Our work uncovers a dual-component pleiotropic regulation of host inflammation and immunity by MOCCI (C15ORF48) for safeguarding the host during infection and inflammation.
Mito-SEPs are small peptides that can modulate oxidative metabolism in mitochondria. Here the authors show that C15ORF48 encodes a mito-SEP, MOCCI, capable of altering mitochondria respiration to suppress inflammation, while
C15ORF48
3’ untranslated region also contains a miRNA, miR-147b, that synergizes with MOCCI to modulate host anti-viral responses.