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INNATE IMMUNITY 3
RIG-I-Like Receptors
RIG-I-like receptors (RLRs), also known as RIG-I-like helicases (RLHs)
constitute a family of cytoplasmic RNA helicases that are critical for host
antiviral responses. RIG-I (retinoic-acid-inducible protein 1, also known as
Ddx58) and MDA-5 (melanoma-differentiation-associated gene 5, also
known as Ifih1 or Helicard) sense double-stranded RNA (dsRNA), a
replication intermediate for RNA viruses, leading to production of type I
interferons (IFNs) in infected cells 1 . Viral dsRNA is also recognized by Toll-
Like receptor 3 (TLR3) which is expressed on the cell surface membrane
or endosomes. Recognition of dsRNA by RIG-I/MDA-5 or TLR3 is cell-type
dependent. Studies of RIG-I- and MDA-5-deficient mice have revealed that
conventional dendritic cells (DCs), macrophages and fibroblasts isolated
from these mice have impaired IFN induction after RNA virus infection,
while production of IFN is still observed in plasmacytoid DCs (pDCs) 2 . Thus
in cDCs, macrophages and fibroblasts, RLRs are the major sensors for viral
infection, while in pDCs, TLRs play a more important role.
RIG-I and MDA-5 contain a DExD/H box RNA helicase and two caspase
recruiting domain (CARD)-like domains. The helicase domain interacts with
dsRNA, whereas the CARD domains are required to relay the signal.
Despite the overall structural similarity between these two sensors, they
detect distinct viral species. RIG-I participates in the recognition of
Paramyxoviruses (Newcastle disease virus (NDV), Sendai virus (SeV)),
Rhabdoviruses (vesicular stomatitis virus (VSV)), Flaviviruses (hepatitis C
(HCV)) and Orthomyxoviruses (Influenza), whereas MDA-5 is essential for
the recognition of Picornaviruses (encephalo-myocarditis virus (EMCV))
and poly(I:C), a synthetic analog of viral dsRNA 3 . Notably, RIG-I binds
specifically to single stranded RNA containing 5’-triphosphate such as viral
RNA and in vitro-transcribed long dsRNA 4 . Mammalian RNA is either
capped or contains base modifications suggesting that RIG-I is able to
discriminate between self and non-self RNA. Recently Kato et al., showed
by using poly(I:C) treated with RNase III that RIG-I binds preferentially to
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short dsRNA while MDA-5 recognizes preferentially long dsRNA 5 .
Although RIG-I and MDA-5 recognize different ligands, they share common
signaling features. Upon recognition of dsRNA, they are recruited by the
adaptor IPS-1 (also known as MAVS, CARDIF or VISA) to the outer
membrane of the mitochondria leading to the activation of several
transcription factors including IRF3, IRF7 and NF-kB 6 . IRF3 and IRF7 control
the expression of type I IFNs, while NF-kB regulates the production of
inflammatory cytokines. IRF3 and IRF7 activation involves TNF (tumor
necrosis factor) receptor-associated factor 3 (TRAF3), NAK-associated
protein 1 (NAP1), TANK and the protein kinase TANK-binding kinase 1
(TBK1) or IkB kinase epsilon (IKKε) 6-8 . Recently, DDX3, a DEAD box
helicase, was shown to interact with TBK1/IKKε 9 . IPS-1 interacts also with
Fas-associated-death-domain (FADD) and receptor interacting protein 1
(RIP1) which induces the activation of the NF-kB pathway 6-8, 10 .
Because the production of cytokines is closely controlled, the RIG-I/
MDA-5 pathway is also strictly regulated. A third RLR has been described:
laboratory of genetics and physiology 2 (LGP2). LGP2 contains a RNA
binding domain but lacks the CARD domains and thus acts as a negative
feedback regulator of RIG-I and MDA-5. LGP2 appears to exert this activity
at multiple levels by i) competitively sequestering dsRNA, ii) forming a
protein complex with IPS-1, and/or iii) binding directly to RIG-I through a
repressor domain 11-13 . Many other molecules seem to be involved in the
negative control of RIG-I/MDA-5-induced IFN production. Dihydroxyacetone
kinase (DAK), A20, ring-finger protein 125 (RNF125), suppressor
of IKKε (SIKE), and peptidyl-propyl isomerase 1 (Pin1), have been recently
described as physiological suppressors of the RIG-I/MDA-5 signaling
pathway. Furthermore, some viral proteases have been identified, such as
NS3/NS4A of the hepatitis C virus, that inactivate RIG-I/MDA-5 signaling
by targeting IPS-1 as effective means to evade innate immunity.
1. Yoneyama M. & Fujita T., 2007. Function of RIG-I-like Receptors in Antiviral Innate
Immunity. J. Biol. Chem. 282: 15315-15318. 2. Kato H. et al., 2005. Cell type-specific
involvement of RIG-I in antiviral response. Immunity. 23(1):19-28. 3. Kawai T. & Akira S.,
2007. Antiviral signaling through pattern recognition receptors. J Biochem. 141(2):137-45.
4. Pichlmair A. et al., 2006. RIG-I-mediated antiviral responses to single-stranded RNA
bearing 5'-phosphates. Science 314:997-1001. 5. Kato H. et al., 2008. Length-dependent
recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and
melanoma differentiation-associated gene 5. J Exp Med. 205(7):1601-10. 6. Kawai T. et al.,
2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.
Nat Immunol. 6(10):981-988 7. Saha SK. et al., 2006. Regulation of antiviral responses by a
direct and specific interaction between TRAF3 and Cardif. Embo J. 25:3257-3263. 8. Sasai
M. et al., 2006. NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic
pathways in type I IFN induction. J Immunol. 177:8676-8683. 9. Schröder M, et al, 2008. Viral
targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation.
EMBO J. 27(15):2147-57. 10. Takahashi K. et al., 2006. Roles of caspase-8 and caspase-10 in
innate immune responses to double-stranded RNA. J Immunol. 176:4520-4524. 11.
Yoneyama M. et al., 2005. Shared and unique functions of the DExD/H-box helicases RIG-
I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 175:2851-58. 12. Komuro A. &
Horvath CM., 2006. RNA- and virus-independent inhibition of antiviral signaling by RNA
helicase LGP2. J Virol. 80(24): 12332-12342. 13. Saito T. et al., 2007. Regulation of innate
antiviral defenses through a shared repressor domain in RIG-I and LGP2. PNAS. 104(2):582-
587.