Editors' ChoiceRNA Stability

Linking RNA Turnover to the Ubiquitin Cycle

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Science's STKE  26 Feb 2002:
Vol. 2002, Issue 121, pp. tw89
DOI: 10.1126/stke.2002.121.tw89

Regulation of messenger RNA (mRNA) stability is one mechanism by which cells can alter their protein constituents rapidly. The AU-rich element (ARE) in the 3′ untranslated region (UTR) of mRNAs promotes degradation. Laroia et al. investigated the role that ubiquitination and the proteasome play in controlling ARE-mediated RNA instability. Cells were transfected with a reporter gene containing a functional ARE or a mutated ARE, the so-called GC reporter, and either the ubiquitin-specific processing protease (UBP) UBPY or UNP. UBPY promotes proteasome-mediated degradation by recycling ubiquitin from degraded peptide fragments; UNP inhibits degradation by removing ubiquitin from native or insufficiently denatured proteins. In addition to monitoring the expression of the reporter genes, the amount of p53 (a ubiquitinated, unstable protein) and eIF4 (a stable, nonubiquitinated protein) were also monitored. Coexpression of the reporter with UBPY promoted degradation of the ARE reporter transcript and inhibited expression of the reporter protein, and coexpression of UNP inhibited ARE-mediated mRNA degradation and increased expression of the reporter protein. Neither UNP nor UBPY affected expression from or stability of the GC reporter transcript. Overwhelming the cell with ARE-containing transcripts can inhibit ARE-mediated degradation. Overexpression of UBPY can overcome this inhibition, suggesting that ubiquitination may be limiting in this situation. Stimulation of ARE-mediated degradation by UBPY was blocked if the cells were treated with a drug to inhibit the proteasome; thus, it is ubiquitin-mediated protein degradation that is important for ARE-mediated mRNA instability. These results were all obtained in transfected cells with reporter constructs; it will be interesting to see if the deubiquitinating proteins (many of which are encoded by ARE-containing transcripts) regulate mRNA stability in vivo.

G. Laroia, B. Sarkar, R. J. Schneider, Ubiquitin-dependent mechanism regulates rapid turnover of AU-rich cytokine mRNAs. Proc. Natl. Acad. Sci. U.S.A. 99, 1842-1846 (2002). [Abstract] [Full Text]

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