TY - JOUR
T1 - Inefficient SRP interaction with a nascent chain triggers a MRNA quality control pathway
AU - Karamyshev, Andrey L.
AU - Patrick, Anna E.
AU - Karamysheva, Zemfira N.
AU - Griesemer, Dustin S.
AU - Hudson, Henry
AU - Tjon-Kon-Sang, Sandra
AU - Nilsson, Ingmarie
AU - Otto, Hendrik
AU - Liu, Qinghua
AU - Rospert, Sabine
AU - Von Heijne, Gunnar
AU - Johnson, Arthur E.
AU - Thomas, Philip J.
N1 - Funding Information:
We thank Xuecheng Ye for recombinant human Ago2 purification; Yiwei Miao and Yuanlong Shao for SRP, microsomes, and εANB-Lys-tRNA amb preparation for some experiments; Tara Hessa for introducing some mutations into the PPL gene; Yuh Min Chook for the plasmid containing pyruvate kinase gene. Research reported in this publication was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health R37DK049835 and CFF grants to P.J.T.; by National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under award number R01GM26494 and Robert A. Welch Foundation Chair grant BE-0017 to A.E.J.; grants SFB 746, Forschergruppe 967, and EXC 294 to S.R.; by the Swedish Cancer Foundation, the Swedish Research Council, the Swedish Foundation for Strategic Research, the European Research Council (ERC-2008-AdG 232648) and the Knut and Alice Wallenberg Foundation to G.v.H.; the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), Magn. Bergvalls Stiftelse and the Carl Trygger Foundation to I.M.N. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2014
Y1 - 2014
N2 - 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).
AB - 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).
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U2 - 10.1016/j.cell.2013.12.017
DO - 10.1016/j.cell.2013.12.017
M3 - Article
C2 - 24439374
AN - SCOPUS:84892768018
SN - 0092-8674
VL - 156
SP - 146
EP - 157
JO - Cell
JF - Cell
IS - 1-2
ER -