Zhang et al. 2023 (PRJNA957283)

Title	Human SAMD9 is a Virus-Activatable Anticodon Nuclease Inhibiting Codon-Specific Protein Synthesis
Organism
Number of Samples	4
Release Date	2023/04/19 00:00
Sequencing Types
Protocol Details

GWIPS-viz	Trips-Viz

Title
Authors	Zhang F,Ji Q,Chaturvedi J,Morales M,Mao Y,Meng X,Dong L,Deng J,Qian SB,Xiang Y
Journal	Science advances
Publication Date	2023 Jun 9
Abstract	As a defense strategy against viruses or competitors, some microbes use anticodon nucleases (ACNases) to deplete essential tRNAs, effectively halting global protein synthesis. However, this mechanism has not been observed in multicellular eukaryotes. Here, we report that human SAMD9 is an ACNase that specifically cleaves phenylalanine tRNA (tRNA Phe ), resulting in codon-specific ribosomal pausing and stress signaling. While SAMD9 ACNase activity is normally latent in cells, it can be activated by poxvirus infection or rendered constitutively active by SAMD9 mutations associated with various human disorders, revealing tRNA Phe depletion as an antiviral mechanism and a pathogenic condition in SAMD9 disorders. We identified the N-terminal effector domain of SAMD9 as the ACNase, with substrate specificity primarily determined by a eukaryotic tRNA Phe -specific 2'- O -methylation at the wobble position, making virtually all eukaryotic tRNA Phe susceptible to SAMD9 cleavage. Notably, the structure and substrate specificity of SAMD9 ACNase differ from known microbial ACNases, suggesting convergent evolution of a common immune defense strategy targeting tRNAs.
PMC	PMC10246899
PMID	37285440
DOI

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