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The EF-Hand Protein CALML6 Suppresses Antiviral Innate Immunity by Impairing IRF3 Dimerization.

Abstract
The transcription factor IRF3 is phosphorylated in response to viral infection, and it subsequently forms a homodimer and translocates into the nucleus to induce the transcription of genes important for antiviral immunity, such as type I interferons (IFNs). This multistep process is essential for host defense against viral infection, but its regulation remains elusive. Here, we report that the EF-hand protein calmodulin-like 6 (CALML6) directly bound to the phosphorylated serine-rich (SR) region of IRF3 and impaired its dimerization and nuclear translocation. Enforced CALML6 expression suppressed viral infection-induced production of IFN-β and expression of IFN-stimulated genes (ISGs), whereas CALML6 deficiency had the opposite effect. In addition, impaired IFN-β and ISG expression in bone-marrow-derived macrophages and tissues of CALML6 transgenic mice promoted viral replication. These findings identify a phosphorylation-dependent negative feedback loop that maintains the homeostasis of antiviral innate immunity.
AuthorsZiyang Wang, Chunjie Sheng, Chen Yao, Hongyuan Chen, Dan Wang, Shuai Chen
JournalCell reports (Cell Rep) Vol. 26 Issue 5 Pg. 1273-1285.e5 (01 29 2019) ISSN: 2211-1247 [Electronic] United States
PMID30699354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Chemical References
  • Antiviral Agents
  • CALML6 protein, human
  • Calcium-Binding Proteins
  • Interferon Regulatory Factor-3
  • Interferon Type I
Topics
  • Animals
  • Antiviral Agents (metabolism)
  • Calcium-Binding Proteins (chemistry, deficiency, metabolism)
  • Cytoplasm (metabolism)
  • EF Hand Motifs
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 (metabolism)
  • Interferon Type I (metabolism)
  • Mice, Transgenic
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Protein Multimerization
  • Signal Transduction
  • Virus Replication

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