Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity.
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.
Lee, CQE; Kerouanton, B; Chothani, S; Zhang, S; Chen, Y; Mantri, CK; Hock, DH; Lim, R; Nadkarni, R; Huynh, VT; Lim, D; Chew, WL; Zhong, FL; Stroud, DA; Schafer, S; Tergaonkar, V; St John, AL; Rackham, OJL; Ho, L
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