Structure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control

Abstract

Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. However, enzymes that are responsible for this event have not been fully identified in high eukaryotes. Here, we report a mammalian tRNA/rRNA-targeting endoribonuclease: SLFN13, a member of the Schlafen family. Structural study reveals a unique pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N′-domain that may clamp base-paired RNAs. SLFN13 is able to digest tRNAs and rRNAs in vitro, and the endonucleolytic cleavage dissevers 11 nucleotides from the 3′-terminus of tRNA at the acceptor stem. The cytoplasmically localised SLFN13 inhibits protein synthesis in 293T cells. Moreover, SLFN13 restricts HIV replication in a nucleolytic activity-dependent manner. According to these observations, we term SLFN13 RNase S13. Our study provides insights into the modulation of translational machinery in high eukaryotes, and sheds light on the functional mechanisms of the Schlafen family.

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

“…In light of this we hypothesize that several eukaryotic Smr proteins, 12 290 295 300 305 310 especially the expanded versions, might function beyond translation surveillance as effectors deployed against viral or parasitic RNA. This is consistent with the discovery of a comparable role for the structurally related Schlafen domain in tRNA processing and retroviral RNA restriction (Li et al 2012;Yang et al 2018), as well as numerous studies showing that cellular RNA processing and translation surveillance factors have antiviral functions (Toh-E et al 1978;Garcia et al 2014;Balistreri et al 2014).…”

“…This aspartate is near a histidine in NONU-1 and forms the conserved DxH motif. More distant branches of the IF3-C fold include domains that bind, cleave, or process RNA, including the RNAseG/E nucleases (Fukui et al 2008), the synaptojanin/calcineurin domain phosphoesterases and nucleases , the Schlafen domain endoribonucleases (Makarova et al 2001;Li et al 2018;Yang et al 2018), and the RtcA RNA end cyclases ( Figure S3B, (Palm et al 2000)).…”

The role of ANGIOGENIN, or lack thereof, in the generation of stress-induced tRNA halves and of smaller tRNA fragments that enter Argonaute complexes

“…For example, In Tetrahymena, S. cerevisiae and Arabidopsis, stress-induced generation of tRNA halves has been attributed to the RNase T2 family (12,68,69). In mammalian cells, other RNases have also been described to cleave tRNAs, such as Dicer (70-72), RNase 1 (36), RNase L (73) and Schlafen13/SFLN13 (74). RNase L was suggested to act independently from ANG by cleaving anticodon loop of tRNA Pro , tRNA His and tRNA Gln (73).…”

Schlafen 11 Restricts Flavivirus Replication

“…Slfn11 binds to tRNAs and counteracts the up-regulation of the tRNA repertoire induced by HIV-1 infection that promotes translation of the codon-biased viral genome[4]. The anti-viral mechanism of Slfn11 seems to involve a tRNA nucleolytic activity recently described in Slfn13[7]. Eight out of nine residues implicated in the tRNA nucleolytic activity of Slfn13[7] are conserved in Slfn11, and these two proteins share an overall homology of 83%.…”

“…The anti-viral mechanism of Slfn11 seems to involve a tRNA nucleolytic activity recently described in Slfn13[7]. Eight out of nine residues implicated in the tRNA nucleolytic activity of Slfn13[7] are conserved in Slfn11, and these two proteins share an overall homology of 83%. This enzymatic activity is required for Slfn13 to restrict HIV-1 infection.…”