Reactome | PDE12 cleaves 2'-5' oligoadenylates

PDE12 cleaves 2'-5' oligoadenylates

Stable Identifier

R-HSA-9009950

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Viral infection produces dsRNA that activates OAS isozymes to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate (2-5A). Latent ribonuclease L (RNase L) binds 2-5A and oligomerizes into an active complex capable of cleaving ssRNA into retinoic acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome-activating small RNAs (Malathi K et al. 2007; Chakrabarti A et al. 2015). Activation of RNase L can be attenuated by 2′-phosphodiesterase (PDE12)- mediated degradation of 2-5A. PDE12 is an endonuclease/exonuclease/phosphatase family member of deadenylases with both 3’,5’- and 2’,5’-phosphodiesterase activities. PDE12 localizes to the mitochondrial matrix and, in addition to degrading 2-5A, removes poly(A) tails from some mitochondrial mRNAs (Kubota K et al. 2004; Poulsen JB et al. 2011; Rorbach J et al. 2011; Silverman RH & Weiss SR 2014; Wood ER et al. 2015). The 2H phosphoesterase, AKAP7, is an unrelated nuclear enzyme that also degrades 2-5A (Gusho E et al. 2014). Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases (each with two conserved histidine motifs) that degrade 2-5A and antagonize RNase L mediated antiviral activity (Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017).

Literature References

PubMed ID	Title	Journal	Year
26055709	The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors Bledsoe, R, Wood, ER, Xia, B, Deng, H, Kryn, LH, Ding, Y, Harris-Gurley, S, Chai, J, Nichols, J, Nartey, E, Sheahan, T, Wisely, B, Shotwell, JB, Nolte, RT, Tai, V, Daka, P, Rise, C, You, S, Wang, L, Smith, D, Tomberlin, G, Prabhu, N, Dickson, H, Taylor, JD	J. Biol. Chem.	2015
15231837	Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferon Kawaguchi, J, Furukawa, H, Matsuoka, T, Ozeki, Y, Yamashita, M, Iijima, Y, Hara, A, Yoshimura, C, Ichikawa, K, Kubota, K, Nakahara, K, Haruyama, H, Fujita, Y, Ohtsuka, T, Yoshida, S	J. Biol. Chem.	2004