A circRNA-derived IRES-like element enables programmable translational activation of the endogenous chaperone HSP90
- 1Italian Institute of Technology
Abstract
Circular RNAs (circRNAs) are covalently closed transcripts that lack a 5' cap, consequently their translation depends on cap-independent initiation, in most cases through Internal Ribosome Entry Sites (IRESs). Whereas IRES-mediated translation has been studied almost exclusively in cis, the use of IRES-containing circRNAs to activate translation of an independent mRNA in trans has only recently begun to be explored. Here, we characterize SynFarsa, a synthetic circRNA-derived IRES-like element that promotes cap-lindependent translation in mouse and human cells. We engineered SynFarsa into a trans-acting regulator by fusing it to a short antisense sequence complementary to a selected region of a target mRNA. This reproduces the architecture of a circular SINEUP, in which IRES activity promotes translation in trans of a transcript recognized through antisense complementarity. Directing this construct to the hsp90 3'UTR increased HSP90 protein levels approximately 1.6-lfold without altering hsp90 mRNA abundance, whereas the hsp70 3'UTR and the 5'UTRs of both transcripts were not permissive, indicating that activity depends strongly on target site selection. In a FUSP525L neuroblastoma model of Amyotrophic Lateral Sclerosis, this increase in HSP90 was accompanied by a reduction in the number and size of cytoplasmic FUS aggregates. SynFarsa thus provides a circRNA-derived effector domain for targeted translational upregulation of an endogenous protein.
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BibTeX
@misc{aoun2026circrnaderived,
title = {{A circRNA-derived IRES-like element enables programmable translational activation of the endogenous chaperone HSP90}},
author = {G. Aoun and A. Vandelli and R. Delli Ponti and S. Gustincich and E. Bechara and L. Broglia and G. G. Tartaglia},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756760},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756760v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A circRNA-derived IRES-like element enables programmable translational activation of the endogenous chaperone HSP90
AU - G. Aoun
AU - A. Vandelli
AU - R. Delli Ponti
AU - S. Gustincich
AU - E. Bechara
AU - L. Broglia
AU - G. G. Tartaglia
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756760
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756760v1
AB - Circular RNAs (circRNAs) are covalently closed transcripts that lack a 5' cap, consequently their translation depends on cap-independent initiation, in most cases through Internal Ribosome Entry Sites (IRESs). Whereas IRES-mediated translation has been studied almost exclusively in cis, the use of IRES-containing circRNAs to activate translation of an independent mRNA in trans has only recently begun to be explored. Here, we characterize SynFarsa, a synthetic circRNA-derived IRES-like element that promotes cap-lindependent translation in mouse and human cells. We engineered SynFarsa into a trans-acting regulator by fusing it to a short antisense sequence complementary to a selected region of a target mRNA. This reproduces the architecture of a circular SINEUP, in which IRES activity promotes translation in trans of a transcript recognized through antisense complementarity. Directing this construct to the hsp90 3'UTR increased HSP90 protein levels approximately 1.6-lfold without altering hsp90 mRNA abundance, whereas the hsp70 3'UTR and the 5'UTRs of both transcripts were not permissive, indicating that activity depends strongly on target site selection. In a FUSP525L neuroblastoma model of Amyotrophic Lateral Sclerosis, this increase in HSP90 was accompanied by a reduction in the number and size of cytoplasmic FUS aggregates. SynFarsa thus provides a circRNA-derived effector domain for targeted translational upregulation of an endogenous protein.
ER -