Research ArticleImmunology

DDAH2 suppresses RLR-MAVS–mediated innate antiviral immunity by stimulating nitric oxide–activated, Drp1-induced mitochondrial fission

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Science Signaling  13 Apr 2021:
Vol. 14, Issue 678, eabc7931
DOI: 10.1126/scisignal.abc7931

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Dialed down by DDAH2

Viral RNAs stimulate innate immune responses by activating RIG-I–like receptors (RLRs) that cause the aggregation of the adaptor protein MAVS on mitochondria. Huang et al. identified dimethylarginine dimethylaminohydrolase 2 (DDAH2) as a negative regulator of RLR-mediated antiviral responses in mouse and human cells. Viral infection induced DDAH2 to translocate to mitochondria, where it stimulated the nitric oxide (NO)–dependent activation of the mitochondrial fission protein Drp1. The resulting mitochondrial fragmentation blocked MAVS-dependent antiviral signaling. Mice lacking DDAH2 showed improved antiviral responses. RLR signaling also negatively regulated DDAH2 activity, suggesting that DDAH2 is important for fine-tuning cellular antiviral responses.

Abstract

The RIG-I–like receptor (RLR) signaling pathway is pivotal for innate immunity against invading viruses, and dysregulation of this molecular cascade has been linked to various diseases. Here, we identified dimethylarginine dimethylaminohydrolase 2 (DDAH2) as a potent regulator of the RLR-mediated antiviral response in human and mouse. Overexpression of DDAH2 attenuated RLR signaling, whereas loss of DDAH2 function enhanced RLR signaling and suppressed viral replication ex vivo and in mice. Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1), which promoted mitochondrial fission and blocked the activation of innate immune responses mediated by mitochondrial antiviral signaling (MAVS). TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. Our study thus identifies a reciprocal inhibitory loop between the DDAH2-NO cascade and the RLR signaling pathway that fine-tunes the antiviral immune response.

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