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

2026 · doi:10.64898/2026.02.03.703619
preprint OA: closed
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⚙ AI-generated summary by claude@2026-07, 2026-07-15 ⓘ

SLFN14 represses protein synthesis by selectively cleaving type II tRNAs, and inherited thrombocytopenia mutations alter this specificity, leading to ribosome stalling and cell death.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-15 · read from full text ⓘ

The paper investigates how SLFN14, an interferon-inducible, ribosome-associated endoribonuclease, represses translation and how disease-linked mutations cause autosomal dominant inherited thrombocytopenia. Using mechanistic experiments, the authors find that SLFN14 selectively cleaves type II tRNAs, leading to ribosome stalling at codons decoded by those tRNAs, which triggers global translational arrest, stress signaling, and cell death; the major limitation is that the work is focused on molecular mechanisms rather than detailed clinical platelet phenotyping. The study further shows that thrombocytopenia-linked mutations shift SLFN14 RNA substrate specificity by enhancing degradation of type II tRNAs while reducing cleavage of rRNA. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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.
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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. Competing Interest Statement The authors have declared no competing interest.

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