Inefficient SRP interaction with a nascent chain triggers a MRNA quality control pathway

Andrey L. Karamyshev, Anna E. Patrick, Zemfira N. Karamysheva, Dustin S. Griesemer, Henry Hudson, Sandra Tjon-Kon-Sang, Ingmarie Nilsson, Hendrik Otto, Qinghua Liu, Sabine Rospert, Gunnar Von Heijne, Arthur E. Johnson, Philip J. Thomas

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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 mechanism of translational quality control, in which specific mRNA degradation preemptively regulates aberrant protein production (RAPP).

Original languageEnglish
Pages (from-to)146-157
Number of pages12
JournalCell
Volume156
Issue number1-2
DOIs
StatePublished - 2014

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