Selective targeting of type II tRNAs underlies SLFN14-mediated translational repression and its dysregulation by thrombocytopenia-linked mutations

Abstract Schlafens (SLFNs) are interferon-inducible regulators of RNA metabolism and cell fate. SLFN14 is a ribosome-associated endoribonuclease whose pathogenic variants cause autosomal dominant inherited thrombocytopenia (IT), but the underlying disease mechanism has been unclear. We show that SLFN14 represses global protein synthesis through selective cleavage of type II tRNAs. IT-linked mutations alter RNA substrate specificity, enhancing degradation of type II tRNAs while reducing rRNA cleavage. This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death. These findings define the molecular basis of SLFN14-associated thrombocytopenia and highlight selective tRNA targeting as a mechanism regulating translation and cell fate.