The SND proteins constitute an alternative targeting route to the endoplasmic reticulum
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The SND proteins constitute an alternative targeting route to the endoplasmic reticulum. / Aviram, Naama; Ast, Tslil; Costa, Elizabeth A; Arakel, Eric C; Chuartzman, Silvia G; Jan, Calvin H; Haßdenteufel, Sarah; Dudek, Johanna; Jung, Martin; Schorr, Stefan; Zimmermann, Richard; Schwappach, Blanche; Weissman, Jonathan S; Schuldiner, Maya.
In: NATURE, Vol. 540, No. 7631, 30.11.2016, p. 134-138.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The SND proteins constitute an alternative targeting route to the endoplasmic reticulum
AU - Aviram, Naama
AU - Ast, Tslil
AU - Costa, Elizabeth A
AU - Arakel, Eric C
AU - Chuartzman, Silvia G
AU - Jan, Calvin H
AU - Haßdenteufel, Sarah
AU - Dudek, Johanna
AU - Jung, Martin
AU - Schorr, Stefan
AU - Zimmermann, Richard
AU - Schwappach, Blanche
AU - Weissman, Jonathan S
AU - Schuldiner, Maya
PY - 2016/11/30
Y1 - 2016/11/30
N2 - 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.
AB - 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.
KW - Endoplasmic Reticulum/metabolism
KW - HEK293 Cells
KW - Humans
KW - Membrane Proteins/metabolism
KW - Phosphate Transport Proteins/metabolism
KW - Protein Domains
KW - Protein Sorting Signals
KW - Protein Transport
KW - Ribosomal Proteins/metabolism
KW - Saccharomyces cerevisiae/cytology
KW - Saccharomyces cerevisiae Proteins/metabolism
KW - Signal Recognition Particle/metabolism
U2 - 10.1038/nature20169
DO - 10.1038/nature20169
M3 - SCORING: Journal article
C2 - 27905431
VL - 540
SP - 134
EP - 138
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7631
ER -