Pri sORF peptides induce selective proteasome-mediated protein processing

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Science  18 Sep 2015:
Vol. 349, Issue 6254, pp. 1356-1358
DOI: 10.1126/science.aac5677

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Small peptide regulates protein activity

Coding and noncoding RNAs can produce peptides from small open reading frames (smORFs), with a variety of mostly unknown functions. Using a genome-wide screen, Zanet et al. show that Polished rice (Pri) smORF peptides control fruit fly development by binding to an E3 ubiquitin ligase. This changes the ligase's selectivity and triggers proteasome-dependent maturation of the developmental transcription factor Shavenbaby. Other smORF peptides may act by a similar mechanism to regulate protein activity.

Science, this issue p. 1356


A wide variety of RNAs encode small open-reading-frame (smORF/sORF) peptides, but their functions are largely unknown. Here, we show that Drosophila polished-rice (pri) sORF peptides trigger proteasome-mediated protein processing, converting the Shavenbaby (Svb) transcription repressor into a shorter activator. A genome-wide RNA interference screen identifies an E2-E3 ubiquitin-conjugating complex, UbcD6-Ubr3, which targets Svb to the proteasome in a pri-dependent manner. Upon interaction with Ubr3, Pri peptides promote the binding of Ubr3 to Svb. Ubr3 can then ubiquitinate the Svb N terminus, which is degraded by the proteasome. The C-terminal domains protect Svb from complete degradation and ensure appropriate processing. Our data show that Pri peptides control selectivity of Ubr3 binding, which suggests that the family of sORF peptides may contain an extended repertoire of protein regulators.

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