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Review
. 2017 Feb;8(2):83-89.
doi: 10.1007/s13238-016-0303-4. Epub 2016 Aug 9.

The emerging roles of the DDX41 protein in immunity and diseases

Yan Jiang  1 , Yanping Zhu  1 , Zhi-Jie Liu  1   2 , Songying Ouyang  3   4
Affiliations
Review

The emerging roles of the DDX41 protein in immunity and diseases

Yan Jiang et al. Protein Cell. 2017 Feb.

Abstract

RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons (IFN). After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutations in DDX41 gene are identified from myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML) patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survival at all stages throughout the life cycle of the fly.

Keywords: DDX41; RNA helicases; acute myeloid leukemia; innate immunity; myelodysplastic syndrome.

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Figures

Figure 1
Figure 1
The signaling pathway of DDX41 in innate immunity. After infection, virus and bacteria release dsDNA or c-di-GMP to cells. DDX41 is then phosphorylated by BTK kinase at Y414 site and activated. The activated DDX41 can detect foreign PAMPs with DEAD domain, and then activate STING. Activated STING translocates from the endoplasmic reticulum (ER) to Golgi apparatus and interacts with TBK1 (Ouyang et al., 2012). The STING-TBK1 complex is required for the activation of TBK1 and the subsequent phosphorylation and nuclear translocation of IRF3, ultimately leading to expression of type I interferons. After immune response, DDX41 is ubiquitinated by Trim 21 at Lys9 and Lys115 sites, leading to degradation in proteasome
Figure 2
Figure 2
The amino acids conservation of human DDX41 DEAD and helicase domains. Graphical representation of the amino acids conservation using the predicted structure of human DDX41 is shown. Mutations related with MDS/AML are labeled. The color scale is based upon the level of conservation as determined by the ConSurf server. Category 9 corresponds to fully conserved residues. Small ribbon diagrams are shown at the top
Figure 3
Figure 3
The phylogenetic tree of DDX41 among different species. The sequences of indicated DDX41 proteins from different species are downloaded from GenBank. The tree is generated using MEGA5 software (http://www.megasoftware.net/) with Neighbor Joining method. Length of branch represents divergence and numbers on branches are indicated as percentage of bootstrap values in 1000 sampling replicates
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