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Nature. 2016 Nov 30;540(7631):134-138. doi: 10.1038/nature20169.

The SND proteins constitute an alternative targeting route to the endoplasmic reticulum.

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Department of Cellular and Molecular Pharmacology, UCSF California Institute for Quantitative Biomedical Research and Howard Hughes Medical Institute, San Francisco, California 94158-2330, USA.
3
Department of Molecular Biology, University Medical Center Göttingen, 37073 Göttingen, Germany.
4
Department of Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg, Germany.
5
Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

Abstract

In eukaryotes, up to one-third of cellular proteins are targeted to the endoplasmic reticulum, where they undergo folding, processing, sorting and trafficking to subsequent endomembrane compartments. Targeting to the endoplasmic reticulum has been shown to occur co-translationally by the signal recognition particle (SRP) pathway or post-translationally by the mammalian transmembrane recognition complex of 40 kDa (TRC40) and homologous yeast guided entry of tail-anchored proteins (GET) pathways. Despite the range of proteins that can be catered for by these two pathways, many proteins are still known to be independent of both SRP and GET, so there seems to be a critical need for an additional dedicated pathway for endoplasmic reticulum relay. We set out to uncover additional targeting proteins using unbiased high-content screening approaches. To this end, we performed a systematic visual screen using the yeast Saccharomyces cerevisiae, and uncovered three uncharacterized proteins whose loss affected targeting. We suggest that these proteins work together and demonstrate that they function in parallel with SRP and GET to target a broad range of substrates to the endoplasmic reticulum. The three proteins, which we name Snd1, Snd2 and Snd3 (for SRP-independent targeting), can synthetically compensate for the loss of both the SRP and GET pathways, and act as a backup targeting system. This explains why it has previously been difficult to demonstrate complete loss of targeting for some substrates. Our discovery thus puts in place an essential piece of the endoplasmic reticulum targeting puzzle, highlighting how the targeting apparatus of the eukaryotic cell is robust, interlinked and flexible.

Comment in

PMID:
27905431
PMCID:
PMC5513701
DOI:
10.1038/nature20169
[Indexed for MEDLINE]
Free PMC Article

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