USP44 positively regulates innate immune response to DNA viruses through deubiquitinating MITA

PLoS Pathog. 2020 Jan 22;16(1):e1008178. doi: 10.1371/journal.ppat.1008178. eCollection 2020 Jan.

Abstract

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/- mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Viruses / immunology*
  • Deubiquitinating Enzyme CYLD / metabolism
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Stability
  • Signal Transduction
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination

Substances

  • Membrane Proteins
  • STING1 protein, human
  • USP20 protein, human
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD
  • USP44 protein, human
  • Ubiquitin Thiolesterase

Grants and funding

This study was supported by National Science Fund for Distinguished Young Scholars (31425010, awarded to Y.Y.W.), the Strategic Priority Research Program (XDB29010302, awarded to Y.Y.W.), the National Natural Science Foundation of China (31621061, awarded to Y.Y.W., 31770946, awarded to Y.Y.), Key Research Programs of Frontier Science (2017YFA0505800, awarded to Y.Y.W.) funded by Chinese Academy of Sciences and the Ministry of Science and Technology of China (2015CB554302, awarded to Y.Y.W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.