[{"date_updated":"2026-09-09T11:31:04Z","date_created":"2026-08-30T22:01:44Z","author":[{"first_name":"Rajagopal","full_name":"Varada, Rajagopal","last_name":"Varada"},{"full_name":"Leuchtenberger, Alina F.","last_name":"Leuchtenberger","first_name":"Alina F."},{"last_name":"Vesely","full_name":"Vesely, Cornelia","first_name":"Cornelia"},{"id":"36FA4AFA-F248-11E8-B48F-1D18A9856A87","full_name":"Kaczmarek, Beata M","last_name":"Kaczmarek","first_name":"Beata M"},{"first_name":"Hamid","last_name":"Mansouri Khosravi","full_name":"Mansouri Khosravi, Hamid"},{"full_name":"Mandl, Therese C.","last_name":"Mandl","first_name":"Therese C."},{"full_name":"Milanovic, Katarina","last_name":"Milanovic","first_name":"Katarina"},{"last_name":"Honarmand Tamizkar","full_name":"Honarmand Tamizkar, Kasra","first_name":"Kasra"},{"full_name":"Rajendra, Vinod","last_name":"Rajendra","first_name":"Vinod"},{"first_name":"Hannes","last_name":"Senoner","full_name":"Senoner, Hannes"},{"first_name":"Linda","full_name":"Steinbichl, Linda","last_name":"Steinbichl"},{"full_name":"Borojevic, Marija","last_name":"Borojevic","first_name":"Marija"},{"first_name":"Andy","last_name":"Sombke","full_name":"Sombke, Andy"},{"full_name":"Schmidt, Katy","last_name":"Schmidt","first_name":"Katy"},{"first_name":"Margret","full_name":"Eckhard, Margret","last_name":"Eckhard"},{"first_name":"Ivo L.","last_name":"Hofacker","full_name":"Hofacker, Ivo L."},{"full_name":"Walkley, Carl","last_name":"Walkley","first_name":"Carl"},{"full_name":"Heraud-Farlow, Jacki E.","last_name":"Heraud-Farlow","first_name":"Jacki E."},{"first_name":"Ernesto","full_name":"Picardi, Ernesto","last_name":"Picardi"},{"full_name":"Bernecky, Carrie A","last_name":"Bernecky","id":"2CB9DFE2-F248-11E8-B48F-1D18A9856A87","first_name":"Carrie A","orcid":"0000-0003-0893-7036"},{"first_name":"Michael F.","last_name":"Jantsch","full_name":"Jantsch, Michael F."}],"doi":"10.1093/nar/gkag845","quality_controlled":"1","external_id":{"pmid":["42635125"]},"intvolume":"        54","OA_place":"publisher","department":[{"_id":"CaBe"},{"_id":"GradSch"}],"publisher":"Oxford University Press","researchdata_availability":"yes","status":"public","article_processing_charge":"Yes","das_tickbox":"1","acknowledgement":"This work was supported by Austrian Science Fund project F80-07 to M.F.J., F80-03 to C.B., and ZK57-B28 to C.V.; National Health and Medical Research Council Australia (NHMRC; GNT2018098 to C.R.W.). The work was supported in part by the Victorian State Government Operational Infrastructure Support Scheme to St Vincent’s Institute and Hudson Institute of Medical Research. R.V. and A.L. were supported by Doc Fund/DOC32 of the Austrian Science Fund. Funding to pay the Open Access publication charges for this article was provided by Austrian Science Fund. For open access purposes, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.","OA_type":"gold","supplementarymaterial":"yes","title":"Distinguishing self from non-self RNA by editing-specific inosine patterns","file":[{"file_id":"22872","checksum":"319904a237f73dcc55daa4a56baa98fa","content_type":"application/pdf","success":1,"file_size":6016116,"relation":"main_file","access_level":"open_access","creator":"dernst","date_created":"2026-09-09T11:29:49Z","date_updated":"2026-09-09T11:29:49Z","file_name":"2026_NucleicAcidsResearch_Varada.pdf"}],"abstract":[{"text":"The cytoplasmic antiviral sensor MDA5 is activated by double-stranded RNAs. Endogenous double-stranded RNAs are modified by the A-to-I RNA-editing ADAR family to prevent activation of MDA5. In vivo, cytoplasmic ADAR1p150 is critically required to suppress MDA5 activation, yet the editing signature of all ADAR isoforms is strongly overlapping in mice. Further, it is not clear how A-to-I modifications in dsRNA prevent MDA5 activation. Here we show that 3′ UTRs harboring inverted repeats activate MDA5 in vitro and in cells. In vitro editing by either ADAR isoform leads to editing at overlapping hotspot regions and prevents MDA5 activation in vitro and in cells. Remarkably, only inosines introduced by RNA editing are capable of suppressing MDA5 activation, while replacing guanosines with inosines during in vitro transcription has no impact on MDA5 activation. A comparison of inosines introduced by ADAR1p150 in vitro, in cells, and in vivo suggests that a small number of A-to-I conversions may be critically required to suppress MDA5 activation. As those critical editing events are predominantly altering A:U basepairs into I:U wobble basepairs, we suggest that the helical distortion introduced by those wobble pairs may prevent MDA5 polymerization and thus downstream activation of the type I interferon response.","lang":"eng"}],"publication_identifier":{"eissn":["1362-4962"]},"oa_version":"Published Version","day":"09","language":[{"iso":"eng"}],"file_date_updated":"2026-09-09T11:29:49Z","citation":{"ama":"Varada R, Leuchtenberger AF, Vesely C, et al. Distinguishing self from non-self RNA by editing-specific inosine patterns. <i>Nucleic Acids Research</i>. 2026;54(16). doi:<a href=\"https://doi.org/10.1093/nar/gkag845\">10.1093/nar/gkag845</a>","ieee":"R. Varada <i>et al.</i>, “Distinguishing self from non-self RNA by editing-specific inosine patterns,” <i>Nucleic Acids Research</i>, vol. 54, no. 16. Oxford University Press, 2026.","chicago":"Varada, Rajagopal, Alina F. Leuchtenberger, Cornelia Vesely, Beata M Kaczmarek, Hamid Mansouri Khosravi, Therese C. Mandl, Katarina Milanovic, et al. “Distinguishing Self from Non-Self RNA by Editing-Specific Inosine Patterns.” <i>Nucleic Acids Research</i>. Oxford University Press, 2026. <a href=\"https://doi.org/10.1093/nar/gkag845\">https://doi.org/10.1093/nar/gkag845</a>.","mla":"Varada, Rajagopal, et al. “Distinguishing Self from Non-Self RNA by Editing-Specific Inosine Patterns.” <i>Nucleic Acids Research</i>, vol. 54, no. 16, gkag845, Oxford University Press, 2026, doi:<a href=\"https://doi.org/10.1093/nar/gkag845\">10.1093/nar/gkag845</a>.","short":"R. Varada, A.F. Leuchtenberger, C. Vesely, B.M. Kaczmarek, H. Mansouri Khosravi, T.C. Mandl, K. Milanovic, K. Honarmand Tamizkar, V. Rajendra, H. Senoner, L. Steinbichl, M. Borojevic, A. Sombke, K. Schmidt, M. Eckhard, I.L. Hofacker, C. Walkley, J.E. Heraud-Farlow, E. Picardi, C. Bernecky, M.F. Jantsch, Nucleic Acids Research 54 (2026).","apa":"Varada, R., Leuchtenberger, A. F., Vesely, C., Kaczmarek, B. M., Mansouri Khosravi, H., Mandl, T. C., … Jantsch, M. F. (2026). Distinguishing self from non-self RNA by editing-specific inosine patterns. <i>Nucleic Acids Research</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/nar/gkag845\">https://doi.org/10.1093/nar/gkag845</a>","ista":"Varada R, Leuchtenberger AF, Vesely C, Kaczmarek BM, Mansouri Khosravi H, Mandl TC, Milanovic K, Honarmand Tamizkar K, Rajendra V, Senoner H, Steinbichl L, Borojevic M, Sombke A, Schmidt K, Eckhard M, Hofacker IL, Walkley C, Heraud-Farlow JE, Picardi E, Bernecky C, Jantsch MF. 2026. Distinguishing self from non-self RNA by editing-specific inosine patterns. Nucleic Acids Research. 54(16), gkag845."},"volume":54,"fulldoi":"https://doi.org/10.1093/nar/gkag845","oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"journal_article","DOAJ_listed":"1","ddc":["570"],"date_published":"2026-09-09T00:00:00Z","publication_status":"published","has_accepted_license":"1","publication":"Nucleic Acids Research","project":[{"grant_number":"F8003","_id":"8dc144d4-16d5-11f0-9cad-9d9e86aea1f7","name":"RNAdeco: decorating RNA for a purpose/ P03- Roles of A-to-I editing in dsRNA recognition"}],"tmp":{"short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"month":"09","PlanS_conform":"1","scopus_import":"1","article_type":"original","article_number":"gkag845","year":"2026","_id":"22772","dataavailabilitystatement":"Sequencing data has been deposited at GEO and is available under accession number GSE293616.\r\nEditing analysis of protected dsRNA is available in GitHub, https://github.com/BioinfoUNIBA/Mouse-dsRNA-mda5, and Zenodo, https://doi.org/10.5281/zenodo.17876716.","issue":"16","pmid":1},{"year":"2025","pmid":1,"_id":"18778","tmp":{"short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"project":[{"grant_number":"P34185","_id":"c08a6700-5a5b-11eb-8a69-82a722b2bc30","name":"Regulation of mammalian transcription by noncoding RNA"}],"scopus_import":"1","article_type":"original","month":"04","isi":1,"publication_status":"published","date_published":"2025-04-01T00:00:00Z","page":"607-612","type":"journal_article","ddc":["570"],"publication":"Nature Structural & Molecular Biology","has_accepted_license":"1","oa":1,"fulldoi":"https://doi.org/10.1038/s41594-024-01448-7","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","day":"01","publication_identifier":{"eissn":["1545-9985"],"issn":["1545-9993"]},"oa_version":"Published Version","volume":32,"citation":{"ista":"Tluckova K, Kaczmarek BM, Testa Salmazo AP, Bernecky C. 2025. Mechanism of mammalian transcriptional repression by noncoding RNA. Nature Structural &#38; Molecular Biology. 32, 607–612.","short":"K. Tluckova, B.M. Kaczmarek, A.P. Testa Salmazo, C. Bernecky, Nature Structural &#38; Molecular Biology 32 (2025) 607–612.","mla":"Tluckova, Katarina, et al. “Mechanism of Mammalian Transcriptional Repression by Noncoding RNA.” <i>Nature Structural &#38; Molecular Biology</i>, vol. 32, Springer Nature, 2025, pp. 607–12, doi:<a href=\"https://doi.org/10.1038/s41594-024-01448-7\">10.1038/s41594-024-01448-7</a>.","apa":"Tluckova, K., Kaczmarek, B. M., Testa Salmazo, A. P., &#38; Bernecky, C. (2025). Mechanism of mammalian transcriptional repression by noncoding RNA. <i>Nature Structural &#38; Molecular Biology</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41594-024-01448-7\">https://doi.org/10.1038/s41594-024-01448-7</a>","ama":"Tluckova K, Kaczmarek BM, Testa Salmazo AP, Bernecky C. Mechanism of mammalian transcriptional repression by noncoding RNA. <i>Nature Structural &#38; Molecular Biology</i>. 2025;32:607-612. doi:<a href=\"https://doi.org/10.1038/s41594-024-01448-7\">10.1038/s41594-024-01448-7</a>","chicago":"Tluckova, Katarina, Beata M Kaczmarek, Anita P Testa Salmazo, and Carrie Bernecky. “Mechanism of Mammalian Transcriptional Repression by Noncoding RNA.” <i>Nature Structural &#38; Molecular Biology</i>. Springer Nature, 2025. <a href=\"https://doi.org/10.1038/s41594-024-01448-7\">https://doi.org/10.1038/s41594-024-01448-7</a>.","ieee":"K. Tluckova, B. M. Kaczmarek, A. P. Testa Salmazo, and C. Bernecky, “Mechanism of mammalian transcriptional repression by noncoding RNA,” <i>Nature Structural &#38; Molecular Biology</i>, vol. 32. Springer Nature, pp. 607–612, 2025."},"language":[{"iso":"eng"}],"file_date_updated":"2025-04-16T08:17:27Z","article_processing_charge":"Yes (in subscription journal)","file":[{"date_updated":"2025-04-16T08:17:27Z","file_name":"2025_NatureStrucMolBiol_Tluckova.pdf","date_created":"2025-04-16T08:17:27Z","creator":"dernst","access_level":"open_access","relation":"main_file","file_size":9306639,"success":1,"content_type":"application/pdf","file_id":"19573","checksum":"2919b30b271f395888e880076a680d73"}],"abstract":[{"text":"Transcription by RNA polymerase II (Pol II) can be repressed by noncoding RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs repress transcription remains unclear. Here we present cryogenic-electron microscopy structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA and RNA bind to Pol II during transcription elongation. Further, we show how distinct domains of the general transcription factor TFIIF control repressive activity. Together, we reveal how a noncoding RNA can regulate mammalian gene expression.","lang":"eng"}],"title":"Mechanism of mammalian transcriptional repression by noncoding RNA","related_material":{"record":[{"id":"14644","status":"public","relation":"earlier_version"}]},"OA_type":"hybrid","acknowledgement":"We thank the members of the Bernecky laboratory for helpful discussions and A. Hlavata for providing Pol II for use in the fluorescence anisotropy binding assay. We thank V.-V. Hodirnau for SerialEM data collection and support with EPU data collection. We thank D. Slade (Max Perutz Laboratories and Medical University of Vienna, Vienna, Austria) for the wild-type TFIIF expression plasmid. We thank N. Thompson and R. Burgess (McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA) for the 8WG16 hybridoma cell line. We thank C. Plaschka and M. Loose for critical reading of the manuscript. This work was supported by Austrian Science Fund (FWF) grant no. P34185 (DOI 10.55776/P34185) (C.B.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This research was further supported by the Scientific Service Units of ISTA through resources provided by the Laboratory Support Facility, Electron Microscopy Facility, Scientific Computing and the Preclinical Facility.","publisher":"Springer Nature","APC_amount":"12348 EUR","status":"public","author":[{"last_name":"Tluckova","full_name":"Tluckova, Katarina","id":"4AC7D980-F248-11E8-B48F-1D18A9856A87","first_name":"Katarina"},{"last_name":"Kaczmarek","id":"36FA4AFA-F248-11E8-B48F-1D18A9856A87","full_name":"Kaczmarek, Beata M","first_name":"Beata M"},{"first_name":"Anita P","last_name":"Testa Salmazo","id":"41F1F098-F248-11E8-B48F-1D18A9856A87","full_name":"Testa Salmazo, Anita P"},{"first_name":"Carrie A","full_name":"Bernecky, Carrie A","last_name":"Bernecky","id":"2CB9DFE2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0893-7036"}],"date_updated":"2025-11-20T10:28:36Z","date_created":"2025-01-08T11:20:20Z","corr_author":"1","department":[{"_id":"CaBe"}],"OA_place":"publisher","intvolume":"        32","external_id":{"isi":["001390268000001"],"pmid":["39762629"]},"acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"EM-Fac"},{"_id":"ScienComp"},{"_id":"PreCl"}],"quality_controlled":"1","doi":"10.1038/s41594-024-01448-7"},{"publisher":"Institute of Science and Technology Austria","researchdata_availability":"unclear","status":"public","date_updated":"2026-10-02T11:14:50Z","author":[{"full_name":"Kaczmarek, Beata M","last_name":"Kaczmarek","id":"36FA4AFA-F248-11E8-B48F-1D18A9856A87","first_name":"Beata M"}],"date_created":"2024-10-27T07:35:13Z","OA_place":"publisher","corr_author":"1","department":[{"_id":"GradSch"},{"_id":"CaBe"}],"doi":"10.15479/at:ista:18477","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"LifeSc"}],"oa_version":"Published Version","publication_identifier":{"isbn":["978-3-99078-045-9"],"issn":["2663-337X"]},"day":"29","citation":{"ista":"Kaczmarek BM. 2024. Biochemical and structural insights into ADAR1 RNA editing. Institute of Science and Technology Austria.","chicago":"Kaczmarek, Beata M. “Biochemical and Structural Insights into ADAR1 RNA Editing.” Institute of Science and Technology Austria, 2024. <a href=\"https://doi.org/10.15479/at:ista:18477\">https://doi.org/10.15479/at:ista:18477</a>.","ieee":"B. M. Kaczmarek, “Biochemical and structural insights into ADAR1 RNA editing,” Institute of Science and Technology Austria, 2024.","ama":"Kaczmarek BM. Biochemical and structural insights into ADAR1 RNA editing. 2024. doi:<a href=\"https://doi.org/10.15479/at:ista:18477\">10.15479/at:ista:18477</a>","apa":"Kaczmarek, B. M. (2024). <i>Biochemical and structural insights into ADAR1 RNA editing</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:18477\">https://doi.org/10.15479/at:ista:18477</a>","short":"B.M. Kaczmarek, Biochemical and Structural Insights into ADAR1 RNA Editing, Institute of Science and Technology Austria, 2024.","mla":"Kaczmarek, Beata M. <i>Biochemical and Structural Insights into ADAR1 RNA Editing</i>. Institute of Science and Technology Austria, 2024, doi:<a href=\"https://doi.org/10.15479/at:ista:18477\">10.15479/at:ista:18477</a>."},"language":[{"iso":"eng"}],"file_date_updated":"2025-10-29T23:30:02Z","alternative_title":["ISTA Thesis"],"article_processing_charge":"No","supervisor":[{"orcid":"0000-0003-0893-7036","last_name":"Bernecky","full_name":"Bernecky, Carrie A","id":"2CB9DFE2-F248-11E8-B48F-1D18A9856A87","first_name":"Carrie A"}],"doi_confirm":"1","title":"Biochemical and structural insights into ADAR1 RNA editing","abstract":[{"lang":"eng","text":"ADAR1 is broadly expressed across various tissues and is vital in regulating pathways\r\nassociated with innate immune responses. ADAR1 marks double-stranded RNA as \"self\"\r\nthrough its A-to-I editing activity, effectively repressing autoimmunity and maintaining\r\nimmune tolerance. This editing process has been detected at millions of sites across the\r\nhuman genome. However, the mechanism underlying ADAR1's substrate selectivity\r\nproperties remains largely unclear, with much of the current knowledge derived from\r\ncomparisons to its more extensively studied homolog, ADAR2. By studying ADAR1 in complex\r\nwith its RNA substrates and applying a combination of biochemical techniques and structural\r\nstudies using CryoEM, we aim to gain a more comprehensive understanding of the substrate\r\nselectivity characteristics of ADAR1.\r\nIn this thesis, the purification protocol for ADAR1 was successfully optimized, resulting in the\r\nfirst report in the literature to achieve high protein purity and activity. This advancement\r\nenabled the investigation of complex formation between ADAR1 and various RNA substrates,\r\nleading to the identification of optimal conditions for preparing the cryoEM sample. However,\r\ndespite comprehensive optimization of the cryo-EM conditions, the resulting data lacked the\r\ndesired quality, highlighting the need for similar rigorous optimization of the RNA substrates\r\nto facilitate structural studies of the ADAR1-RNA complex. The study was complemented by\r\nAlphaFold predictions, which provided some insights into this mechanism.\r\nMoreover, during this project I established a collaboration with a research group focused on\r\nstudying ADAR homologs. Notably ADAR homologs were identified in bivalve species, and it\r\nwas further demonstrated that ADAR and its A-to-I editing activity are upregulated in Pacific\r\noysters during infections with Ostreid herpesvirus-1—a highly infectious virus that leads to\r\nsignificant losses in oyster populations globally. I successfully purified oyster ADAR and\r\nprepared in vitro edited RNA for nanopore sequencing—a direct sequencing technology\r\ncapable of detecting modified nucleotides without the need for reverse transcription. The\r\ncollaborators initiated optimization of this nanopore-based approach. However, current\r\ntechnological limitations still constrain the reliable detection of modified nucleotides.\r\nThe project also examined the impact of RNA editing on RNA binding and filament formation\r\nby MDA5, a key cytosolic dsRNA sensor that triggers an interferon response. A primary target\r\nof ADAR1's editing activity is RNA derived from repetitive elements present in the genome,\r\nparticularly Alu elements forming double-stranded RNA. When unedited, these RNA\r\nsequences are recognized by MDA5. However, the mechanisms by which MDA5 interacts with\r\nAlu RNAs, as well as the role of A-to-I editing in influencing this binding, are still not well\r\nunderstood.\r\nThe interaction between MDA5 and Alu elements, was successfully established. This was\r\nachieved through the testing of different RNA variants and the evaluation of filament\r\nformation using binding techniques and electron microscopy imaging. This groundwork has\r\nset the conditions for further evaluation using CryoEM. Furthermore, the effects of A-to-I\r\nediting on the binding properties of MDA5 with Alu RNA were investigated. Given the recent\r\nresearch that has provided new insights into MDA5's interaction with dsRNA, it is essential to\r\nrevise the experimental setup to integrate these findings before moving forward with the\r\nCryoEM sample analysis."}],"file":[{"embargo_to":"open_access","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_id":"18485","checksum":"2053294ea4d770c495e4cc501e2a218b","date_created":"2024-10-29T11:56:36Z","file_name":"20241029_PhD_thesis_BKaczmarek.docx","date_updated":"2025-10-29T23:30:02Z","creator":"bkaczmar","access_level":"closed","relation":"source_file","file_size":23136626},{"content_type":"application/pdf","checksum":"8ce857a4cd44b776791eaf180ac9dbb3","file_id":"18486","access_level":"open_access","date_created":"2024-10-29T11:56:44Z","creator":"bkaczmar","embargo":"2025-10-29","file_name":"20241029_PhD_thesis_BKaczmarek.pdf","date_updated":"2025-10-29T23:30:02Z","relation":"main_file","file_size":11707360}],"supplementarymaterial":"unclear","date_published":"2024-10-29T00:00:00Z","publication_status":"published","ddc":["572"],"type":"dissertation","page":"124","has_accepted_license":"1","fulldoi":"https://doi.org/10.15479/at:ista:18477","oa":1,"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","degree_awarded":"PhD","year":"2024","_id":"18477","tmp":{"short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"month":"10"},{"author":[{"orcid":"0000-0003-1365-5631","first_name":"Urban","full_name":"Bezeljak, Urban","id":"2A58201A-F248-11E8-B48F-1D18A9856A87","last_name":"Bezeljak"},{"first_name":"Hrushikesh","full_name":"Loya, Hrushikesh","last_name":"Loya"},{"id":"36FA4AFA-F248-11E8-B48F-1D18A9856A87","last_name":"Kaczmarek","full_name":"Kaczmarek, Beata M","first_name":"Beata M"},{"last_name":"Saunders","full_name":"Saunders, Timothy E.","first_name":"Timothy E."},{"orcid":"0000-0001-7309-9724","id":"462D4284-F248-11E8-B48F-1D18A9856A87","last_name":"Loose","full_name":"Loose, Martin","first_name":"Martin"}],"date_created":"2020-03-12T05:32:26Z","date_updated":"2026-04-08T07:24:55Z","department":[{"_id":"MaLo"},{"_id":"CaBe"}],"intvolume":"       117","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"external_id":{"isi":["000521821800040"],"pmid":["32161136"]},"doi":"10.1073/pnas.1921027117","quality_controlled":"1","publisher":"National Academy of Sciences","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/776567"}],"status":"public","article_processing_charge":"No","abstract":[{"text":"The eukaryotic endomembrane system is controlled by small GTPases of the Rab family, which are activated at defined times and locations in a switch-like manner. While this switch is well understood for an individual protein, how regulatory networks produce intracellular activity patterns is currently not known. Here, we combine in vitro reconstitution experiments with computational modeling to study a minimal Rab5 activation network. We find that the molecular interactions in this system give rise to a positive feedback and bistable collective switching of Rab5. Furthermore, we find that switching near the critical point is intrinsically stochastic and provide evidence that controlling the inactive population of Rab5 on the membrane can shape the network response. Notably, we demonstrate that collective switching can spread on the membrane surface as a traveling wave of Rab5 activation. Together, our findings reveal how biochemical signaling networks control vesicle trafficking pathways and how their nonequilibrium properties define the spatiotemporal organization of the cell.","lang":"eng"}],"title":"Stochastic activation and bistability in a Rab GTPase regulatory network","related_material":{"record":[{"id":"8341","status":"public","relation":"dissertation_contains"}],"link":[{"description":"News on IST Homepage","url":"https://ist.ac.at/en/news/proteins-as-molecular-switches/","relation":"press_release"}]},"day":"24","oa_version":"Preprint","publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"volume":117,"citation":{"chicago":"Bezeljak, Urban, Hrushikesh Loya, Beata M Kaczmarek, Timothy E. Saunders, and Martin Loose. “Stochastic Activation and Bistability in a Rab GTPase Regulatory Network.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2020. <a href=\"https://doi.org/10.1073/pnas.1921027117\">https://doi.org/10.1073/pnas.1921027117</a>.","ieee":"U. Bezeljak, H. Loya, B. M. Kaczmarek, T. E. Saunders, and M. Loose, “Stochastic activation and bistability in a Rab GTPase regulatory network,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 117, no. 12. National Academy of Sciences, pp. 6504–6549, 2020.","ama":"Bezeljak U, Loya H, Kaczmarek BM, Saunders TE, Loose M. Stochastic activation and bistability in a Rab GTPase regulatory network. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2020;117(12):6504-6549. doi:<a href=\"https://doi.org/10.1073/pnas.1921027117\">10.1073/pnas.1921027117</a>","apa":"Bezeljak, U., Loya, H., Kaczmarek, B. M., Saunders, T. E., &#38; Loose, M. (2020). Stochastic activation and bistability in a Rab GTPase regulatory network. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.1921027117\">https://doi.org/10.1073/pnas.1921027117</a>","short":"U. Bezeljak, H. Loya, B.M. Kaczmarek, T.E. Saunders, M. Loose, Proceedings of the National Academy of Sciences of the United States of America 117 (2020) 6504–6549.","mla":"Bezeljak, Urban, et al. “Stochastic Activation and Bistability in a Rab GTPase Regulatory Network.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 117, no. 12, National Academy of Sciences, 2020, pp. 6504–49, doi:<a href=\"https://doi.org/10.1073/pnas.1921027117\">10.1073/pnas.1921027117</a>.","ista":"Bezeljak U, Loya H, Kaczmarek BM, Saunders TE, Loose M. 2020. Stochastic activation and bistability in a Rab GTPase regulatory network. Proceedings of the National Academy of Sciences of the United States of America. 117(12), 6504–6549."},"language":[{"iso":"eng"}],"fulldoi":"https://doi.org/10.1073/pnas.1921027117","oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","date_published":"2020-03-24T00:00:00Z","page":"6504-6549","type":"journal_article","publication":"Proceedings of the National Academy of Sciences of the United States of America","project":[{"name":"Reconstitution of cell polarity and axis determination in a cell-free system","_id":"2599F062-B435-11E9-9278-68D0E5697425","grant_number":"RGY0083/2016"}],"scopus_import":"1","article_type":"original","month":"03","isi":1,"year":"2020","pmid":1,"issue":"12","_id":"7580"}]