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Uncovering Targeting Priority to Yeast Peroxisomes Using an In-Cell Competition Assay

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Uncovering Targeting Priority to Yeast Peroxisomes Using an In-Cell Competition Assay Uncovering targeting priority to yeast peroxisomes using an in-cell competition assay Mira Rosenthala,1, Eyal Metzl-Raza,1, Jérôme Bürgib, Eden Yifracha, Layla Drweshc, Amir Fadela, Yoav Pelegd, Doron Rapaportc, Matthias Wilmannsb,e, Naama Barkaia, Maya Schuldinera,2, and Einat Zalckvara,2 aDepartment of Molecular Genetics, Weizmann Institute of Science, 7610001 Rehovot, Israel; bHamburg Unit c/o DESY, European Molecular Biology Laboratory, 22607 Hamburg, Germany; cInterfaculty Institute of Biochemistry, University of Tübingen, 72074 Tübingen, Germany; dStructural Proteomics Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel; and eUniversity Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany Edited by William A. Prinz, National Institutes of Health, Bethesda, MD, and accepted by Editorial Board Member Tony Hunter July 17, 2020 (received for review November 16, 2019) Approximately half of eukaryotic proteins reside in organelles. To any pathway what all of the proteins that have evolved to be reach their correct destination, such proteins harbor targeting signals optimally targeted by it are, what the various mechanisms by recognized by dedicated targeting pathways. It has been shown that which they do so are, and how this is rewired under the changing differences in targeting signals alter the efficiency in which proteins metabolic conditions of the cell. are recognized and targeted. Since multiple proteins compete for any To study targeting priority for entire pathways and in living single pathway, such differences can affect the priority for which a cells, we developed a systematic tool that is based on high content protein is catered. However, to date the entire repertoire of proteins imaging in the yeast Saccharomyces cerevisiae (hereafter called with targeting priority, and the mechanisms underlying it, have not yeast). As a proof-of-concept, we used the well-described Pex5- been explored for any pathway. Here we developed a systematic tool to study targeting priority and used the Pex5-mediated targeting to mediated pathway that recognizes the PTS1 and targets most – yeast peroxisomes as a model. We titrated Pex5 out by expressing matrix (lumen) peroxisomal proteins (12 14). We expressed to high levels of a Pex5-cargo protein and examined how the localiza- very high levels a synthetic cargo protein with a PTS1 targeting tion of each peroxisomal protein is affected. We found that while signal and systematically examined how the competition over Pex5 most known Pex5 cargo proteins were outcompeted, several cargo affects the localization of each of the known peroxisomal proteins. proteins were not affected, implying that they have high targeting We found that, as expected, the vast majority of PTS1-containing priority. This priority group was dependent on metabolic conditions. proteins were affected by the competition over Pex5. However, a We dissected the mechanism of priority for these proteins and sug- few PTS1 proteins had targeting priority in a manner dependent gest that targeting priority is governed by different parameters, in- on the carbon source consumed. By following up on priority car- cluding binding affinity of the targeting signal to the cargo factor, the goes, we suggest that they use various strategies to gain their number of binding interfaces to the cargo factor, and more. This ap- priority, such as additional binding interface on Pex5 or targeting proach can be modified to study targeting priority in various organ- signals with strong affinity. elles, cell types, and organisms. yeast | peroxisomes | protein targeting | systems cell biology Significance n eukaryotic cells, most proteins are encoded in the nuclear Half of eukaryotic proteins reside in organelles to which they Igenome and are synthesized on cytosolic ribosomes. Approxi- are directed by dedicated targeting pathways, each recogniz- mately half of these proteins require targeting to specific or- ing unique targeting signals. Multiple proteins compete for any ganelles to execute their function (1). Organellar proteins are targeting pathway and might have different priority of recognized and targeted to their correct cellular destination by reaching an organelle. However, the proteins with targeting various targeting pathways (2–4). Defects in protein targeting priority, and the mechanisms underlying it, have not been ex- can lead to diseases that can be caused either by loss of protein plored. We developed a systematic tool to study targeting function at its destination organelle, mistargeting to another priority. We expressed a competitor protein and examined organelle, or by accumulation of proteins in the cytosol, where how it affects the localization of all other proteins targeted by they can misfunction or aggregate (5, 6). the same pathway. We found several proteins with high tar- Most organelle proteins have a targeting signal that is recog- geting priority, dissected the mechanism of priority, and sug- nized by one or more cytosolic targeting factors. The complex of gest that priority is governed by different parameters. This cargo protein with its targeting factor is directionally recruited to approach can be modified to study targeting priority in various the correct organelle by binding receptor proteins on the desti- organelles, cell types, and organisms. nation membrane (4, 7, 8). Many cargo proteins carry the same Author contributions: D.R., M.W., N.B., M.S., and E.Z. designed research; M.R., E.M.-R., type of targeting signal. For example, tens of proteins carry a J.B., E.Y., L.D., A.F., and Y.P. performed research; E.M.-R. analyzed data; and M.R., M.S., peroxisomal targeting signal type I (PTS1), and hundreds of and E.Z. wrote the paper. proteins carry a signal peptide to travel to the endoplasmic re- The authors declare no competing interest. ticulum or a mitochondrial targeting sequence to travel to the This article is a PNAS Direct Submission. W.A.P. is a guest editor invited by the inner mitochondrial compartments. Often proteins with a similar Editorial Board. targeting signal also utilize the same targeting pathway (3). As This open access article is distributed under Creative Commons Attribution-NonCommercial- many proteins are targeted via the same pathway, and the NoDerivatives License 4.0 (CC BY-NC-ND). abundance of the cargo factor may become limiting, it has been 1M.R. and E.M.-R. contributed equally to this work. shown that certain cargo proteins have evolved to have stronger 2To whom correspondence may be addressed. Email: [email protected] or targeting signals than others (9). Moreover, it is clear that some [email protected]. cargo can utilize multiple pathways to ensure optimal targeting, This article contains supporting information online at https://www.pnas.org/lookup/suppl/ whereas others are restricted to a single pathway (4, 10, 11). doi:10.1073/pnas.1920078117/-/DCSupplemental. Despite these anecdotal demonstrations, it is not yet clear for First published August 17, 2020. 21432–21440 | PNAS | September 1, 2020 | vol. 117 | no. 35 www.pnas.org/cgi/doi/10.1073/pnas.1920078117 Downloaded by guest on October 1, 2021 Results (21) were not affected by the mCherry-SKL competitor (SI Ap- Developing a Tool to Study Targeting Priority. As a test case for our pendix,Fig.S2). This gave us an indication that high levels of method of dissecting targeting priority of proteins to organelles, mCherry-SKL do not unspecifically alter peroxisomal physiology we used the Pex5-mediated targeting machinery of peroxisomal nor block the import machinery of matrix proteins. Unexpectedly, proteins in yeast. Pex5 mediates the targeting of most peroxi- Pex18, a coreceptor of Pex7 (22), had reduced localization to somal matrix proteins, mainly through binding to a PTS1 targeting peroxisomes when high levels of the competitor were expressed signal (12, 14). This pathway is a good model as it is well charac- (Dataset S1). This hints that, in addition to the contribution of terized and has a well-known cargo repertoire. To induce conditions Pex18 to Pex7-mediated targeting, Pex18 may also have some in which cargo proteins compete over a limited amount of Pex5, we interplay with the Pex5 targeting machinery in a way that should expressed different levels of the mCherry protein tagged on its be further studied. Conversely, the localization to peroxisomes of carboxy (C′) terminus with a well-studied PTS1 targeting signal (15) the recently identified PTS1 targeting factor, Pex9 (9, 10), and one composed of the last three amino acids serine-lysine-leucine of its cargoes Gto1 (glutathione transferase omega-like 1 protein (mCherry-SKL) that are considered as a canonical targeting signal. 1) was enhanced during competitive conditions rather than being Our rationale was that when the mCherry-SKL is expressed in low reduced (Dataset S1), suggesting that it may function as a back-up amounts, it will not affect targeting of peroxisomal matrix proteins pathway under these conditions. since it will be one of many other cargoes requiring this pathway. Focusing on the Pex5 cargo proteins [19 were correctly lo- However, when mCherry-SKL is expressed in high levels, it will calized to peroxisomes in our collection (18, 23)], we observed compete with other Pex5 cargo proteins. Hence, only proteins that that the localization of most (14 cargo proteins) was affected by the competition and that they accumulated in the cytosol have high targeting priority would still be localized to peroxisomes B (Fig. 1A). (Dataset S1; examples shown in Fig. 2 ). In support of the effect To express high levels of the mCherry-SKL protein, we inte- on Pex5 cargo being a direct result of saturating Pex5 amounts, we found that overexpressing Pex5 could rescue the targeting of grated into the yeast genome multiple copies of the mCherry- such a PTS1 cargo, Pxp1 (SI Appendix, Fig. S3). SKL–encoding gene driven by a strong promoter (15). This has Interestingly, the localization of five Pex5 cargo proteins the advantage of reaching very high expression levels that are not (carnitine acetyl-CoA transferase, Cat2; saccharopine dehydro- reachable using increasing strengths of promoters alone (16).
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