Translation of bi-directional transcripts enhances MHC-I peptide diversity

Area of Science:

• Genomics
• Immunology
• Molecular Biology

Background:

• Antisense transcripts are known regulators of non-coding RNAs.
• The translational potential of antisense transcripts into functional peptides is largely unknown.

Purpose of the Study:

• To investigate the translation of antisense transcripts into functional peptides.
• To identify novel peptides derived from alternative reading frames of bi-directional transcripts.
• To assess the immunogenicity of these novel peptides.

Main Methods:

• RNA sequencing and six-frame database generation.
• Mass spectrometry analysis of peptides isolated from polysomes.
• T cell proliferation assays using peripheral blood mononuclear cells (PBMCs).

Main Results:

• Identified Nascent Pioneer Translation Products (Na-PTPs) from antisense strands.
• Two Na-PTP derived peptides stimulated CD8+ T cell proliferation.
• An antigenic peptide from a reverse strand construct induced CD8+ T cell activation via MHC-I presentation.

Conclusions:

• Bi-directional transcript translation generates antigenic peptides.
• This process contributes to self-discriminating peptide substrates for the MHC-I pathway.
• Findings have implications for understanding immune self-recognition and enhancing immunotherapies.