Role of the novel endoribonuclease SLFN14 and its disease causing mutations in ribosomal degradation

Neil Morgan, Sarah Fletcher, Abdullah Khan, Andrey Pisarev, Vera Pisareva, Andrew Tcherepanov

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
157 Downloads (Pure)

Abstract

Platelets are anucleate and mostly ribosome-free cells within the bloodstream, derived from megakaryocytes within bone marrow and crucial for cessation of bleeding at sites of injury. Inherited thrombocytopenias are a group of disorders characterized by a low platelet count and are frequently associated with excessive bleeding. SLFN14 is one of the most recently discovered genes linked to inherited thrombocytopenia where several heterozygous missense mutations in SLFN14 were identified to cause defective megakaryocyte maturation and platelet dysfunction. Yet, SLFN14 was recently described as a ribosome-associated protein resulting in rRNA and ribosome-bound mRNA degradation in rabbit reticulocytes. To unveil the cellular function of SLFN14 and the link between SLFN14 and thrombocytopenia, we examined SLFN14 (WT/mutants) in in vitro models. Here, we show that all SLFN14 variants co-localize with ribosomes and mediate rRNA endonucleolytic degradation. Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of post-translational degradation due to partial misfolding of the protein. Moreover, all SLFN14 variants tend to form oligomers. These findings could explain the dominant negative effect of heterozygous mutation on SLFN14 expression in
patients’ platelets. Overall we suggest that SLFN14 could be involved in ribosome degradation during platelet formation and maturation.
Original languageEnglish
Pages (from-to)939-949
JournalRNA
Volume24
Issue number7
Early online date20 Apr 2018
DOIs
Publication statusPublished - Jul 2018

Keywords

  • RNA degradation
  • SLFN14
  • endoribonuclease
  • platelet
  • ribonuclease
  • thrombocytopenia

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