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

Hong-Yan Zhang,Dong-Peng Wang,Yan Yang,Wei-Wei Luo,Zhi-Sheng Xu,Bo-Wei Liao,Yong Ran,Yan-Yi Wang,Ekaterina E Heldwein

doi:10.1371/journal.ppat.1008178

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.

Highlights

The innate immune response is the first line of host defense against pathogens
We found that the deubiquitinating enzymes ubiquitin-specific protease 44 (USP44) associates with MITA and removes the K48-linked polyubiquitin chains from MITA, maintains the stability of MITA after DNA virus infection
Deficiency of USP44 results in accelerated degradation of MITA, impaired induction of type I IFNs and proinflammatory cytokines, and increased viral replication. These findings suggest that USP44 is a positive regulator of MITA and plays an important role in the regulation of innate immune response against DNA viruses

Summary

Introduction

The innate immune response is the first line of host defense against pathogens. Germlineencoded pattern recognition receptors (PRRs) recognize conserved molecular motifs of pathogens called pathogen-associated molecular patterns (PAMPs) and trigger a series of signaling events, leading to induction of type I IFNs, proinflammatory cytokines and downstream antiviral effector proteins, which eventually inhibit the replication of pathogens and eliminate the infected cells [1,2,3,4].Viral nucleic acids act as typical PAMPs that trigger innate immune response. The nucleotidyltransferase family protein cyclic GMP-AMP (cGAMP) synthase (cGAS) is identified as a cytosolic DNA sensor that induces interferons irrespective of cell type or DNA sequence [15,16,17]. Once associated with cGAMP, MITA traffics from ER through Golgi apparatus to perinuclear microsomal compartments [19, 24, 25]. During this process, MITA recruits the TANK-binding kinase 1 (TBK1) and is phosphorylated by TBK1, which is important for MITA to recruit interferon regulatory factor 3 (IRF3) [18, 24]. Phosphorylated IRF3 form dimers and translocate to the nucleus, leading to the induction of type I IFNs and downstream effector genes [26, 27]

Methods

Results

Discussion

Conclusion