HEPN RNases - an Emerging Class of Functionally Distinct RNA Processing and Degradation Enzymes

Overview

Journal Crit Rev Biochem Mol Biol

Publisher Informa Healthcare

Specialties Biochemistry
Molecular Biology

Date 2020 Dec 22

PMID 33349060

Citations 10

Authors

Monica C Pillon

Jacob Gordon

Meredith N Frazier

Robin E Stanley

Affiliations

Soon will be listed here.

Abstract

HEPN (Higher Eukaryotes and Prokaryotes Nucleotide-binding) RNases are an emerging class of functionally diverse RNA processing and degradation enzymes. Members are defined by a small α-helical bundle encompassing a short consensus RNase motif. HEPN dimerization is a universal requirement for RNase activation as the conserved RNase motifs are precisely positioned at the dimer interface to form a composite catalytic center. While the core HEPN fold is conserved, the organization surrounding the HEPN dimer can support large structural deviations that contribute to their specialized functions. HEPN RNases are conserved throughout evolution and include bacterial HEPN RNases such as CRISPR-Cas and toxin-antitoxin associated nucleases, as well as eukaryotic HEPN RNases that adopt large multi-component machines. Here we summarize the canonical elements of the growing HEPN RNase family and identify molecular features that influence RNase function and regulation. We explore similarities and differences between members of the HEPN RNase family and describe the current mechanisms for HEPN RNase activation and inhibition.

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References

Naka K, Koga M, Yonesaki T, Otsuka Y . RNase HI stimulates the activity of RnlA toxin in Escherichia coli. Mol Microbiol. 2013; 91(3):596-605. DOI: 10.1111/mmi.12479. View

Pickar-Oliver A, Gersbach C . The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol. 2019; 20(8):490-507. PMC: 7079207. DOI: 10.1038/s41580-019-0131-5. View

Otsuka Y, Koga M, Iwamoto A, Yonesaki T . A role of RnlA in the RNase LS activity from Escherichia coli. Genes Genet Syst. 2007; 82(4):291-9. DOI: 10.1266/ggs.82.291. View

Coelho D, Domingos P . Physiological roles of regulated Ire1 dependent decay. Front Genet. 2014; 5:76. PMC: 3997004. DOI: 10.3389/fgene.2014.00076. View

Chakrabarti A, Jha B, Silverman R . New insights into the role of RNase L in innate immunity. J Interferon Cytokine Res. 2010; 31(1):49-57. PMC: 3021357. DOI: 10.1089/jir.2010.0120. View

Rath S, Prangley E, Donovan J, Demarest K, Wingreen N, Meir Y . Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response. Mol Cell. 2019; 75(6):1218-1228.e6. PMC: 6754276. DOI: 10.1016/j.molcel.2019.07.027. View

Korennykh A, Egea P, Korostelev A, Finer-Moore J, Zhang C, Shokat K . The unfolded protein response signals through high-order assembly of Ire1. Nature. 2008; 457(7230):687-93. PMC: 2846394. DOI: 10.1038/nature07661. View

Sanches M, Duffy N, Talukdar M, Thevakumaran N, Chiovitti D, Canny M . Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun. 2014; 5:4202. PMC: 4486471. DOI: 10.1038/ncomms5202. View

Amin-Wetzel N, Neidhardt L, Yan Y, Mayer M, Ron D . Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR. Elife. 2019; 8. PMC: 6996924. DOI: 10.7554/eLife.50793. View

10.

Grynberg M, Erlandsen H, Godzik A . HEPN: a common domain in bacterial drug resistance and human neurodegenerative proteins. Trends Biochem Sci. 2003; 28(5):224-6. DOI: 10.1016/S0968-0004(03)00060-4. View

11.

Winther K, Gerdes K . Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA. Proc Natl Acad Sci U S A. 2011; 108(18):7403-7. PMC: 3088637. DOI: 10.1073/pnas.1019587108. View

12.

Naka K, Qi D, Yonesaki T, Otsuka Y . RnlB Antitoxin of the Escherichia coli RnlA-RnlB Toxin-Antitoxin Module Requires RNase HI for Inhibition of RnlA Toxin Activity. Toxins (Basel). 2017; 9(1). PMC: 5308261. DOI: 10.3390/toxins9010029. View

13.

Zhang C, Konermann S, Brideau N, Lotfy P, Wu X, Novick S . Structural Basis for the RNA-Guided Ribonuclease Activity of CRISPR-Cas13d. Cell. 2018; 175(1):212-223.e17. PMC: 6179368. DOI: 10.1016/j.cell.2018.09.001. View

14.

Barrangou R, Horvath P . A decade of discovery: CRISPR functions and applications. Nat Microbiol. 2017; 2:17092. DOI: 10.1038/nmicrobiol.2017.92. View

15.

Wiseman R, Zhang Y, Lee K, Harding H, Haynes C, Price J . Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1. Mol Cell. 2010; 38(2):291-304. PMC: 2864793. DOI: 10.1016/j.molcel.2010.04.001. View

16.

Ni H, Rui Q, Li D, Gao R, Chen G . The Role of IRE1 Signaling in the Central Nervous System Diseases. Curr Neuropharmacol. 2018; 16(9):1340-1347. PMC: 6251047. DOI: 10.2174/1570159X16666180416094646. View

17.

Korennykh A, Walter P . Structural basis of the unfolded protein response. Annu Rev Cell Dev Biol. 2012; 28:251-77. DOI: 10.1146/annurev-cellbio-101011-155826. View

18.

Cox J, Shamu C, Walter P . Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 1993; 73(6):1197-206. DOI: 10.1016/0092-8674(93)90648-a. View

19.

Murugan K, Babu K, Sundaresan R, Rajan R, Sashital D . The Revolution Continues: Newly Discovered Systems Expand the CRISPR-Cas Toolkit. Mol Cell. 2017; 68(1):15-25. PMC: 5683099. DOI: 10.1016/j.molcel.2017.09.007. View

20.

Burke J, Moon S, Matheny T, Parker R . RNase L Reprograms Translation by Widespread mRNA Turnover Escaped by Antiviral mRNAs. Mol Cell. 2019; 75(6):1203-1217.e5. PMC: 6754297. DOI: 10.1016/j.molcel.2019.07.029. View