Journal
CELL
Volume 156, Issue 1-2, Pages 146-157Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.12.017
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health [R37DK049835]
- CFF grants
- National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health [R01GM26494]
- Robert A. Welch Foundation [BE-0017, SFB 746, Forschergruppe 967, EXC 294]
- Swedish Cancer Foundation
- Swedish Research Council
- Swedish Foundation for Strategic Research
- European Research Council [ERC-2008-AdG 232648]
- Knut and Alice Wallenberg Foundation
- Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
- Magn. Bergvalls Stiftelse
- Carl Trygger Foundation
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Misfolded proteins are often cytotoxic, unless cellular systems prevent their accumulation. Data presented here uncover a mechanism by which defects in secretory proteins lead to a dramatic reduction in their mRNAs and protein expression. When mutant signal sequences fail to bind to the signal recognition particle (SRP) at the ribosome exit site, the nascent chain instead contacts Argonaute2 (Ago2), and the mutant mRNAs are specifically degraded. Severity of signal sequence mutations correlated with increased proximity of Ago2 to nascent chain and mRNA degradation. Ago2 knockdown inhibited degradation of the mutant mRNA, while overexpression of Ago2 or knockdown of SRP54 promoted degradation of secretory protein mRNA. The results reveal a previously unappreciated general mechanismof translational quality control, in which specific mRNA degradation preemptively regulates aberrant protein production (RAPP).
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