MDA-5 is structurally related to RIG-I, as it also contains two CARD domains and a helicase domain. MDA-5 was originally identified as a type I IFN-induc-ible molecule mediating cell cycle arrest and apoptosis in melanoma cells (hence the name melanoma differentiation antigen 5) (Kang et al. 2002, 2004; Kovacsovics et al. 2002). A first indication of a role for MDA-5 in virus recognition came from the observation that a paramyxoviral protein that mediated immune evasion bound to MDA-5 (Andrejeva et al. 2004). In overexpression experiments, MDA-5 was shown to bind poly I:C, and enhanced the interferon response to poly I:C as well as several viruses. Conversely, siRNA mediated knock-down blocked type I IFN induction in response to these stimuli (Yoneyama et al. 2005). MDA-5 was then shown to play an essential role in the detection of Picornaviruses such as encephalomyocarditis virus (EMCV) or Theiler's virus (Gitlin et al. 2006; Kato et al. 2006). In addition, mice deficient in MDA-5 were found to be highly susceptible to EMCV. Although the nature of the natural RNA ligand that engages MDA-5 has so far remained obscure, a surprising observation was that cells derived from MDA-5-deficient mice, as well as MDA-5-/- mice stimulated in vivo were found unable to mount a type I IFN response to poly I:C, establishing MDA-5, rather than the several other receptors that bind, or have been shown to be activated by poly I:C, as the dominant receptor mediating the interferon response to poly I:C (Gitlin et al. 2006; Kato et al. 2006). However, the natural viral ligand for MDA-5 has not yet been identified.
In addition to RIG-I and MDA-5, another cytosolic receptor may exist for detecting DNA. Until recently TLR9 was the only innate sensor for detecting microbial DNA. Recent studies indicate that DNA is detected in the cytosol independently of TLR9 (Okabe et al. 2005; Stetson and Medzhitov 2006), but the receptor has not been identified yet. The cytosolic receptor mediating recognition of B-form DNA, unlike RIG-I and MDA-5, signals independently of IPS-1.
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