Short open reading frame genes in innate immunity: from discovery to characterization

Trends Immunol. 2022 Sep;43(9):741-756. doi: 10.1016/ Epub 2022 Aug 11.


Next-generation sequencing (NGS) technologies have greatly expanded the size of the known transcriptome. Many newly discovered transcripts are classified as long noncoding RNAs (lncRNAs) which are assumed to affect phenotype through sequence and structure and not via translated protein products despite the vast majority of them harboring short open reading frames (sORFs). Recent advances have demonstrated that the noncoding designation is incorrect in many cases and that sORF-encoded peptides (SEPs) translated from these transcripts are important contributors to diverse biological processes. Interest in SEPs is at an early stage and there is evidence for the existence of thousands of SEPs that are yet unstudied. We hope to pique interest in investigating this unexplored proteome by providing a discussion of SEP characterization generally and describing specific discoveries in innate immunity.

Keywords: Bifunctional genes; Innate immunity; Short open reading frames (sORFs).

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Immunity, Innate
  • Open Reading Frames
  • Peptides*
  • RNA, Long Noncoding*
  • Transcriptome


  • Peptides
  • RNA, Long Noncoding