Submitted July 29, 2008
Accepted September 29, 2008
Incomplete T cell receptor 
peptides target the mitochondrion and induce apoptosis
Nir Shani, Hila Rubin-Lifshitz, Yifat Peretz-Cohen, Ketty Shkolnik, Vera Shinder, Michal Cohen-Sfady, Yaron Shav-Tal, Mira Barda-Saad, and Dov Zipori*
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
* Corresponding author; email: dov.zipori{at}weizmann.ac.il.
The default pathway of cell surface T cell receptor (TCR) complex formation, and the subsequent transport to the membrane, is thought to entail endoplasmic reticulum (ER) localization followed by proteasome degradation of the unassembled chains. We demonstrate herein an alternative pathway; short, incomplete peptide versions of TCR
, naturally occur in the thymus. Such peptides, that have minimally lost the leader sequence, or have been massively truncated, leaving only the very C terminus intact, are sorted preferentially to the mitochondrion. As a consequence of the mitochondrial localization, apoptotic cell death is induced. Structure function analysis showed that both the specific localization and induction of apoptosis are dependent upon the transmembrane domain (TMD) and associated residues at the COOH-terminus of TCR. Truncated forms of TCR, such as the short peptides that we detected in the thymus, may be products of protein degradation within thymocytes. Alternatively, they may occur through the translation of truncated mRNAs resulting from unfruitful rearrangement or from germline transcription. It is proposed that mitochondria serve as a sub-cellular sequestration site for incomplete TCR molecules.
