RNASEL binds 2'-5' oligoadenylate

Stable Identifier
R-HSA-8985123
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Rotavirus A
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Ribonuclease L (RNASEL) gene encodes an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase RNase L that functions in the interferon (IFN) antiviral response (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Upon activation by viral double-stranded RNA, 5'-triphosphorylated 2'-5'-linked oligoadenylates (2-5A) are synthesized by one of several 2'-5' oligoadenylate synthetases (OAS). The 2-5A binds to monomeric, inactive RNase L causing it to dimerize through the ANK domains (Dong B & Silverman RH 1995; Tanaka N et al. 2004, 2005; Han Y et al., 2012). Activated RNase L cleaves single-stranded viral and cellular RNA, predominantly after UpU and UpA dinucleotides (Floyd-Smith G et al. 1981; Wreschner DH et al. 1981). The triadenylate form of 2-5A is the minimal active molecule, however, longer 2',5'-oligoadenylates retain the ability to activate RNase L (Dong B et al. 1994).

RNase L possesses nine ankyrin repeats (the 9th being incomplete) in the N-terminus, and pseudokinase and nuclease domains in the C-terminus, which is also termed the kinase-extension nuclease (KEN) domain (Hassel BA et al. 1993; Tanaka N et al. 2004; Han Y et al. 2014; Huang H et al. 2014). The monomeric RNase L lacks nucleolytic activity, however, deletion of ankyrin repeats caused constitutive, albeit reduced, ribonuclease activity (Dong B et al. 1997). Crystal structure data indicate that 2-5A binds to the second and fourth ankyrin repeats and the pseudokinase domain (Tanaka N et al. 2004; Huang H et al. 2014; Han Y et al. 2014). These interactions, in conjunction with binding between the pseudokinase domains of the two protomers, mediate dimerization and enzymatic activation within minutes (Huang H et al. 2014; Han Y et al. 2012, 2014). Once active, RNase L cleaves ssRNA, including cellular mRNA and rRNA as well as microbial RNAs. In uninfected cells RNase L interacts with the actin-binding protein filamin A (FLNA) to modulate the actin cytoskeleton and inhibit virus entry into cells (Malathi K et al. 2014; Ezelle HJ et al. 2016). Upon infection and activation of its enzymatic activity by 2-5A, RNase L dissociates from FLNA to mediate its antiviral signaling (Malathi K et al. 2014; Ezelle HJ et al. 2016).

Literature References
PubMed ID Title Journal Year
24578532 Structure of human RNase L reveals the basis for regulated RNA decay in the IFN response

Han, Y, Donovan, J, Rath, S, Whitney, G, Chitrakar, A, Korennykh, A

Science 2014
26760998 The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response

Ezelle, HJ, Malathi, K, Hassel, BA

Int J Mol Sci 2016
25352621 RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entry

Malathi, K, Siddiqui, MA, Dayal, S, Naji, M, Ezelle, HJ, Zeng, C, Zhou, A, Hassel, BA

MBio 2014
23084743 Innate immune messenger 2-5A tethers human RNase L into active high-order complexes

Han, Y, Whitney, G, Donovan, J, Korennykh, A

Cell Rep 2012
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