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The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling

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  • Young-Suk Yoo

    (Ajou University School of Medicine, Graduate School of Ajou University
    Graduate School of Ajou University)

  • Yong-Yea Park

    (Ajou University School of Medicine, Graduate School of Ajou University)

  • Jae-Hoon Kim

    (College of Veterinary Medicine (BK21 Plus Program), Chungnam National University)

  • Hyeseon Cho

    (Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH)

  • Song-Hee Kim

    (Ajou University School of Medicine, Graduate School of Ajou University)

  • Ho-Soo Lee

    (Ajou University School of Medicine, Graduate School of Ajou University
    Graduate School of Ajou University)

  • Tae-Hwan Kim

    (College of Veterinary Medicine (BK21 Plus Program), Chungnam National University)

  • You Sun Kim

    (Ajou University School of Medicine, Graduate School of Ajou University
    Graduate School of Ajou University)

  • Youngsoo Lee

    (Graduate School of Ajou University
    Genomic Instability Research Center, Ajou University School of Medicine)

  • Chul-Joong Kim

    (College of Veterinary Medicine (BK21 Plus Program), Chungnam National University)

  • Jae U Jung

    (Keck School of Medicine, University of Southern California)

  • Jong-Soo Lee

    (College of Veterinary Medicine (BK21 Plus Program), Chungnam National University)

  • Hyeseong Cho

    (Ajou University School of Medicine, Graduate School of Ajou University
    Graduate School of Ajou University
    Genomic Instability Research Center, Ajou University School of Medicine)

Abstract

Mitochondria serve as platforms for innate immunity. The mitochondrial antiviral signalling (MAVS) protein forms aggregates that elicit robust type-I interferon induction on viral infection, but persistent MAVS signalling leads to host immunopathology; it remains unknown how these signalling aggregates are resolved. Here we identify the mitochondria-resident E3 ligase, MARCH5, as a negative regulator of MAVS aggregates. March5+/− mice and MARCH5-deficient immune cells exhibit low viral replication and elevated type-I interferon responses to RNA viruses. MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. MARCH5, but not its RING mutant (MARCH5H43W), reduces the level of MAVS aggregates. MARCH5 transfers ubiquitin to Lys7 and Lys500 of MAVS and promotes its proteasome-mediated degradation. Our results indicate that MARCH5 modulates MAVS-mediated antiviral signalling, preventing excessive immune reactions.

Suggested Citation

  • Young-Suk Yoo & Yong-Yea Park & Jae-Hoon Kim & Hyeseon Cho & Song-Hee Kim & Ho-Soo Lee & Tae-Hwan Kim & You Sun Kim & Youngsoo Lee & Chul-Joong Kim & Jae U Jung & Jong-Soo Lee & Hyeseong Cho, 2015. "The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8910
    DOI: 10.1038/ncomms8910
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