Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.
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).
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address: andrey.karamyshev@utsouthwestern.edu.
Andrey L
AL
Karamyshev
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Anna E
AE
Patrick
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Zemfira N
ZN
Karamysheva
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Dustin S
DS
Griesemer
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Henry
H
Hudson
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Sandra
S
Tjon-Kon-Sang
Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.
IngMarie
I
Nilsson
Institute of Biochemistry and Molecular Biology, ZBMZ, and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
Hendrik
H
Otto
Department of Biochemistry, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Qinghua
Q
Liu
Institute of Biochemistry and Molecular Biology, ZBMZ, and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
Sabine
S
Rospert
Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden; Science for Life Laboratory Stockholm University, Box 1031, 171 21 Solna, Sweden.
Gunnar
G
von Heijne
Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, Texas A&M University, College Station, TX 77843, USA; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA; Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
Arthur E
AE
Johnson
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address: philip.thomas@utsouthwestern.edu.
Philip J
PJ
Thomas
D000595:Amino Acid Sequence; D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D017510:Protein Folding; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D018271:Signal Recognition Particle / Q000378:metabolism*
D060565:Argonaute Proteins; D012333:RNA, Messenger; D018271:Signal Recognition Particle