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

  • Sci Signal. 2021 Apr 13;14(678):eabc7931. doi: 10.1126/scisignal.abc7931.
Shan Huang  1  2 ,  Zexing Li  2 ,  Zewen Wu  1  3 ,  Chang Liu  1  2 ,  Minghang Yu  1 ,  Mingjie Wen  1 ,  Liyun Zhang  4 ,  Xi Wang  5  2  3
Affiliations
  • 1. Department of Immunology, School of Basic Medical Sciences; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory for Cancer Invasion and Metastasis, Department of Oncology, Capital Medical University, Beijing 100069, China.
  • 2. Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 3. Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan 30032, Shanxi, China.
  • 4. Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan 30032, Shanxi, China. [email protected] [email protected].
  • 5. Department of Immunology, School of Basic Medical Sciences; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory for Cancer Invasion and Metastasis, Department of Oncology, Capital Medical University, Beijing 100069, China. [email protected] [email protected].
PMID: 33850055 DOI: 10.1126/scisignal.abc7931
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.