The emerging roles of the DDX41 protein in immunity and diseases
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.
KEYWORDSDDX41 innate immunity RNA helicases myelodysplastic syndrome acute myeloid leukemia
RNA helicases are enzymes that utilize the energy derived from NTP hydrolysis to unwind double-stranded RNA (dsRNA) molecules (Luking et al., 1998) or disrupt RNA-protein interactions (Jankowsky et al., 2001). DExD/H-box helicases comprise the largest SF2 helicase superfamily. Within the DExD/H-box family, the proteins are further classified as DEAD, DEAH, DExH, and DExD helicases based on the amino acid sequence of the conserved motif II (Fullam and Schroder, 2013). DEAD-box proteins, which are named after the strictly conserved sequence Asp-Glu-Ala-Asp (D-E-A-D), are widely found in organisms from bacteria to humans (Linder et al., 1989). They are involved in many aspects of RNA metabolism, such as transcription, pre-mRNA splicing, transport, translation, mRNA decay, and ribosome biogenesis (Rocak and Linder, 2004). The core of DEAD-box proteins consists of two tandem repeats of RecA-like domains, with motifs I, Ia, Ib, II, and III in the N-terminal domain and motifs IV, V, and VI in the C-terminal domain. The DEAD sequence is located in motif II (Caruthers and McKay, 2002). Subsequent studies identified three additional motifs that are characteristic of the DEAD-box proteins, namely the Q-motif (Cordin et al., 2004), GG motif (Schmid and Linder, 1992), and QxxR motif (Caruthers et al., 2000).
Pathogen-associated molecular patterns (PAMPs) of pathogens can be detected by cells of the innate immune response with the help of germline-encoded pattern recognition receptors (PRRs) to induce type I interferons (IFN) (Medzhitov and Janeway, 2000). In recent years it has been reported that several DExD/H-box helicases contribute to antiviral immunity, either by acting as sensors for viral nucleic acids or by facilitating downstream signaling events. The RIG-like helicases (RLHs), including RIG-I, MDA5, and LGP2 are recognized as one of the most important groups of anti-viral PRRs (Schmidt et al., 2012). Another DEAD box helicase, DDX3 is reported to act as a sensor for viral RNA in conjunction with RIG-I and MDA5. The authors proposed that DDX3 can sensitize the RLH system for dsRNA ligands at early stages of infection when levels of RIG-I are still low (Oshiumi et al., 2010). DHX9 is identified as a sensor for dsRNA in myeloid cells (Zhang et al., 2011c), and as a sensor for CpG DNA in plasmacytoid dendritic cells (pDCs) (Kim et al., 2010). DDX1 can directly bind to poly(I:C) (Zhang et al., 2011a). DDX21 and DHX36 are located downstream of DDX1. Both DDX21 and DHX36 interact with the downstream protein TIR-domain-containing-adapter-inducing interferon-β (TRIF). This suggests that DDX1 senses dsRNA and then triggers signaling via DDX21 and DHX36 to TRIF (Zhang et al., 2011a). DDX60 is proved to act in conjunction with RIG-I or MDA5 to mediate responses to viral dsRNA (Miyashita et al., 2011). Besides the involvement in antiviral immune response, DEAD-box proteins also play important roles in virus replication. DDX1 can bind to Hepatitis C virus (HCV) 3′ (+) UTR as well as its reverse complementary 5′ (−) UTR (Tingting et al., 2006), suggesting a possible role in the initiation of HCV RNA replication. DDX1 has also been reported to be important for the human immunodeficiency virus type 1 (HIV-1) replication as it binds to and serves as a cofactor of the HIV-1 Rev protein (Fang et al., 2004). DDX3 is required for HCV RNA replication, wherein the HCV core binds to the C-terminus of DDX3 (Owsianka and Patel, 1999). DDX5 was found to interact with the HCV NS5B protein, and to be important for HCV RNA replication (Goh et al., 2004). Taken together, the DExD/H-box helicases may have a much broader role in innate immunity and cancers than previously appreciated. In this review, we will focus on the functions of DDX41 and its Drosophila homolog Abstrakt (Abs).
FUNCTIONS OF DDX41
Functions of DDX41 in innate immunity
Functions of DDX41 in human diseases
FUNCTIONS OF ABSTRAKT
Abstrakt in Drosophila is the homolog of DDX41, which shares 66% identity and 80% similarity at the amino acid level. The gene was initially identified by a very specific phenotype, the failure of the Bolwig nerve to fasciculate and project normally (Schmucker et al., 1997). Abstrakt is essential for survival at all stages throughout the life cycle of the fly. Mutants show specific defects in many developmental processes, including cell-shape changes, localization of RNA, and apoptosis. Mutations of E236K and V426M show a temperature-sensitive behavior, leading to lethality at 29°C and above (Irion and Leptin, 1999). In 2004, Irion et al. found that Abstrakt has a role in controlling cell polarity and asymmetric cell division in multiple cell types. The Abs protein interacts with insc RNA. Abs mutants show loss of Insc protein levels but no change of insc RNA levels. Although Abs is predicted to participate in RNA metabolism, they demonstrated a novel role for Abs in the post-transcriptional regulation of insc expression (Irion et al., 2004). An unexpected interaction of Abs and Sorting Nexin-2 (SNX2) was found by Johnny K. Ngsee’ group in 2005 (Abdul-Ghani et al., 2005). They found that the N-terminal domain of Abs interacts with the phox homology (PX) domain of SNX2, suggesting that Abs also participates in protein sorting. They also found that Abs might shuttle between the nucleus and cytoplasm with a bias towards the nucleus, and the N-terminal domain is responsible for its nuclear localization. Deletion of this domain in Abs (aa 194–622) resulted in distinct punctate cytoplasmic distribution and loss of nuclear localization (Abdul-Ghani et al., 2005).
In conclusion, although many new roles of DDX41 have been discovered, there are still many problems to be solved, where structural elucidation can have a significant impact. Added importance of structural investigation comes from the indication that DDX41 may function as a tumor suppressor, and could be a good therapeutic target for disease treatment.
This work was supported by the National Basic Research Program (973 Program) (No. 2014CB910400 and 2013CB911103), the National Natural Science Foundation of China (Grants No. 31570875, 31330019, 81590761, 31560727 and 81501353), the Beijing Nova Program (Grant No. Z141102001814020) to S.O., Youth Innovation Promotion Association CAS (Grant No. 2013065) to S.O., and the special project of Ebola virus research from the president foundation of Chinese Academy of Sciences.
MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; BTK, Bruton’s tyrosine kinase; D-E-A-D, Asp-Glu-Ala-Asp; HCV, hepatitis C virus; IFN, interferon; IRF3, interferon regulatory factor 3; mDC, myeloid dendritic cells; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; TRIF, TIR-domain-containing-adapter-inducing interferon-β
COMPLIANCE WITH ETHICS GUIDELINES
Yan Jiang, Zhi-Jie Liu, and Songying Ouyang declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by the any of the authors.
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