Research Article: DDX24 Negatively Regulates Cytosolic RNA-Mediated Innate Immune Signaling

Date Published: October 31, 2013

Publisher: Public Library of Science

Author(s): Zhe Ma, Robert Moore, Xiangxi Xu, Glen N. Barber, Mark T. Heise.

http://doi.org/10.1371/journal.ppat.1003721

Abstract

RIG-I-Like Receptors (RLRs) sense cytosolic viral RNA to transiently activate type I IFN production. Here, we report that a type I IFN inducible DExD/H helicase, DDX24, exerts a negative-regulatory effect on RLR function. Expression of DDX24 specifically suppressed RLR activity, while DDX24 loss, which caused embryonic lethality, augmented cytosolic RNA-mediated innate signaling and facilitated RNA virus replication. DDX24 preferentially bound to RNA rather than DNA species and influenced signaling by associating with adaptor proteins FADD and RIP1. These events preferentially impeded IRF7 activity, an essential transcription factor for type I IFN production. Our data provide a new function for DDX24 and help explain innate immune gene regulation, mechanisms that may additionally provide insight into the causes of inflammatory disease.

Partial Text

The principal purpose of the immediate innate immune response is the rapid synthesis and secretion of type I interferons (IFNβ and IFNα) as well as inducing other key host defense genes [1], [2]. Innate immune signaling is initiated by pattern recognition receptors (PRRs) that specifically recognize pathogen-associated molecular patterns (PAMPs), which are unique to microbes and rarely found in the host [3]. Upon virus infection, virus-associated PAMPs such as genomic DNA or RNA can be recognized by PRRs, which initiate signaling events leading to the synthesis of type I IFN and to the transcription of other IFN-inducible genes (ISG’s) in a paracrine or autocrine manner [1], [3]. Three major PRRs participating in the recognition of viral PAMPs have been identified as the Toll-like receptors (TLRs), retinoic acid-inducible gene I-like (RIG-I) receptors (RLRs) and cytosolic DNA receptors [4]–[6]. TLR3, 7, 8 and 9 are TLRs responsible for recognizing viral nucleic acid species. TLR3 is known to recognize dsRNA, while TLR7 and TLR8 recognize ssRNA, and TLR9 senses unmethylated CpG DNA [3]. The RLR family comprises three receptors, RIG-I, melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) [5]. RIG-I recognizes 5′-triphosphate RNA and short forms of the synthetic dsRNA analog poly I:C, whereas MDA5 is mainly responsible for recognizing longer dsRNA species [7]–[9]. LGP2 has also been shown to exert anti-viral properties [10], [11]. The mechanisms of cytosolic viral DNA recognition is the least characterized pathway but is known to involve AIM2 which activates inflammatory response [12], [13] and STING (TMEM173/MITA/MPYS) which has been shown to be critical for cytosolic DNA triggered type I IFN production as well as pro-inflammatory gene production [14]–[17]. Furthermore, NLRs (nucleotide-binding domain, leucine-rich repeat containing), key modulators of the inflammasome, also recognize dsRNA. Rather than inducing IFN, they are important for triggering IL-1 beta production, and play important roles in the host response to a wide range of microbial pathogens, inflammatory diseases, and autoimmune disorders [18].

It has been previously reported that RIG-I/MDA5 associates with FADD, RIP1 and TRADD in a signaling complex that also involves IPS-1 and which is required for the stimulation of host defense genes [1], [29]. Our data here indicate that an uncharacterized helicase DDX24 may negatively regulate these processes. DDX24 belongs to the DExH/D family, which contains at least 59 proteins conserved from bacteria to humans. DExH/D helicases are broadly involved in many RNA related processes such as transcription, translation, ribosome biogenesis and RNA transportation [37]. In addition, RIG-I, MDA5 and LGP2 have been reported to be key sensors in RNA-virus mediated innate immune signaling processes. However, several other RNA helicases have also been implicated in the regulation of host defense processes such as DHX9, DDX60 and DDX3x which reportedly act as alternate RNA sensors in myeloid dendritic (mDCs) among other cells [38]–[40]. DDX1/DDX21/DHX36 complex may similarly be involved with sensing both short and long poly I:C via the adaptor TRIF [41]. Further, DHX9 and DHX36 have been reported to sense cytosolic CpG-DNA via MyD88 in pDCs [42]. Finally, DDX41 has been reported to sense intracellular DNA [43].

 

Source:

http://doi.org/10.1371/journal.ppat.1003721

 

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