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

Jin Yu Yang ,Fu Xiang Zheng ,Hui Zhang ,Xi Wang ,Jian Feng ,Yi Sheng Li ,Ziqian Fang ,Yi Ping Li ,Bing Yu ,Rui‐Hua Xu ,Xiancai Ma ,Libing Song ,Wei Xie ,Wei Chen ,Yi Luo ,Qian Zhong ,Yang Chen ,Mu‐Sheng Zeng ,Xiang Deng ,Tiebang Kang ,Mei Ling Chen ,Song Gao

doi:10.1038/s41467-018-03544-x

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.

Highlights

Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses
There are ten known or predicted SLFNs in mice which can be categorised into three subgroups by size, whereas only five SLFNs have been identified in humans, and four of them (SLFN5, SLFN11, SLFN13 and SLFN14) belong to the largest subgroup III17 (Supplementary Fig. 1a)
The final model was refined to an Rfree of 0.247 (Table 1, Fig. 1a, b; Supplementary Fig. 1b). 15 vectorencoded residues fused N-terminally to rSLFN1314–353 are clearly discernable in the model

Summary

Introduction

Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. Stress-induced cleavage of tRNA and rRNA in the cytosol is observed in both prokaryotes and eukaryotes, which causes protein synthesis arrest and results in growth inhibition or eventually, cell death[8,9,10]. Few tRNases involved in this process are known in high eukaryotes These enzymes, such as human angiogenin, are normally secreted or sequestered proteins that gain access to cytosolic tRNAs upon cellular stress[8,14,15]. Investigation of the structure and subsequent functional analysis reveals that SLFN13 is a novel tRNA/rRNA-targeting RNase with potent anti-HIV activity. These results expand our vision of translational control in high eukaryotes and functional mechanisms of the Schlafen family

Methods

Results

Conclusion