{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T18:09:40Z","timestamp":1782756580490,"version":"3.54.5"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 114-2321-B-002-022"],"award-info":[{"award-number":["NSTC 114-2321-B-002-022"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Biomed Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The nucleocapsid (N) protein of coronavirus harbors a conserved serine\/arginine (SR)\u2013rich motif whose phosphorylation by GSK-3 is essential for viral transcription and replication. Our previous studies in Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the JHM strain of mouse hepatitis virus revealed a phosphorylation-to-dephosphorylation transition during the viral life cycle, with newly synthesized N highly phosphorylated and virion-associated N hypophosphorylated. Here, we characterize this transition in SARS-CoV-2 and define its functional significance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Utilizing high-resolution gel analysis and the phospho-specific antibody, the phosphorylation levels of SARS-CoV-2 N proteins in the virus-infected Calu-3 cells and secreted virions from culture supernatants were compared between different viral strains. This phosphorylation-to-dephosphorylation transition was also verified in the SARS-CoV-2 virus-like particle (SC2-VLP) platform expressing N, membrane (M), envelope, and spike proteins. In this VLP system, the substantial contribution of N dephosphorylation status to particle secretion, either by blocking GSK-3 activity or phospho-related mutants, was assessed. With different viral structural protein-expressing clones and phosphatase inhibitors, we characterized the key viral factor and host phosphatase to mediate the N dephosphorylation process. Furthermore, we evaluated the antiviral efficacy of phosphatase inhibitors using the virus-infected Calu-3 culture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our results showed that the phosphorylation change of SR motif in N was observed across multiple strains and recapitulated in the SC2-VLP system. GSK-3 inhibition or a phospho-deficient N mutant, but not a phospho-mimetic one, enhanced VLP release, indicating that N dephosphorylation promotes virion secretion. Mechanistically, the M protein, via its C-terminal domain, interacts with phosphorylated N to recruit protein phosphatase 2A (PP2A) to the ERGIC, facilitating N dephosphorylation. Inhibition of PP2A, either by inhibitors or siRNA, impaired the M-induced N dephosphorylation, thereby suppressing viral assembly and progeny virion production. Blockade of PP2A also indirectly reduced N phosphorylation through the Akt-mediated inhibition of GSK-3, resulting in decreased genomic RNA synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, these findings establish N dephosphorylation as a critical regulatory step in SARS-CoV-2 assembly and virion release. In ERGIC, this M protein-mediated process recruits host PP2A to dephosphorylate N, thus supporting PP2A as a promising pan-coronavirus antiviral target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01255-w","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T13:51:04Z","timestamp":1778853064000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SARS-CoV-2 membrane protein recruits PP2A to dephosphorylate the nucleocapsid and promote virion production"],"prefix":"10.1186","volume":"33","author":[{"given":"Sheng-Han","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Ling","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ling","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Jer","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui-Yuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiou-Hwei","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"1255_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/biology12091267","author":"M Andre","year":"2023","unstructured":"Andre M, Lau LS, Pokharel MD, Ramelow J, Owens F, Souchak J, et al. From Alpha to Omicron: how different variants of concern of the SARS-Coronavirus-2 impacted the world. Biology. 2023. https:\/\/doi.org\/10.3390\/biology12091267.","journal-title":"Biology"},{"issue":"3","key":"1255_CR2","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.cell.2020.09.018","volume":"183","author":"H Yao","year":"2020","unstructured":"Yao H, Song Y, Chen Y, Wu N, Xu J, Sun C, et al. Molecular architecture of the SARS-CoV-2 virus. Cell. 2020;183(3):730\u20138. https:\/\/doi.org\/10.1016\/j.cell.2020.09.018.","journal-title":"Cell"},{"key":"1255_CR3","doi-asserted-by":"publisher","first-page":"5309","DOI":"10.1128\/JCM.42.11.5309-5314.2004","volume":"42","author":"Y He","year":"2004","unstructured":"He Y, Zhou Y, Wu H, Kou Z, Liu S, Jiang S. Mapping of antigenic sites on the nucleocapsid protein of the Severe Acute Respiratory Syndrome Coronavirus. J Clin Microbiol. 2004;42:5309\u201314. https:\/\/doi.org\/10.1128\/JCM.42.11.5309-5314.2004.","journal-title":"J Clin Microbiol"},{"key":"1255_CR4","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41467-021-21953-3","volume":"2021","author":"J Cubuk","year":"1936","unstructured":"Cubuk J, Alston JJ, Incicco JJ, Singh S, Stuchell-Brereton MD, Ward MD, et al. The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA. Nat Commun. 1936;2021:12. https:\/\/doi.org\/10.1038\/s41467-021-21953-3.","journal-title":"Nat Commun"},{"key":"1255_CR5","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.chom.2014.09.009","volume":"16","author":"CH Wu","year":"2014","unstructured":"Wu CH, Chen PJ, Yeh SH. Nucleocapsid phosphorylation and RNA helicase DDX1 recruitment enables coronavirus transition from discontinuous to continuous transcription. Cell Host Microbe. 2014;16:462\u201372. https:\/\/doi.org\/10.1016\/j.chom.2014.09.009.","journal-title":"Cell Host Microbe"},{"key":"1255_CR6","doi-asserted-by":"publisher","first-page":"5229","DOI":"10.1074\/jbc.M805747200","volume":"284","author":"CH Wu","year":"2009","unstructured":"Wu CH, Yeh SH, Tsay YG, Shieh YH, Kao CL, Chen YS, et al. Glycogen synthase kinase-3 regulates the phosphorylation of severe acute respiratory syndrome coronavirus nucleocapsid protein and viral replication. J Biol Chem. 2009;284:5229\u201339. https:\/\/doi.org\/10.1074\/jbc.M805747200.","journal-title":"J Biol Chem"},{"key":"1255_CR7","doi-asserted-by":"publisher","first-page":"219","DOI":"10.3389\/fmolb.2020.00219","volume":"7","author":"E Nikolakaki","year":"2020","unstructured":"Nikolakaki E, Giannakouros T. SR\/RS Motifs as Critical Determinants of Coronavirus Life Cycle. Front Mol Biosci. 2020;7:219. https:\/\/doi.org\/10.3389\/fmolb.2020.00219.","journal-title":"Front Mol Biosci"},{"key":"1255_CR8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2113401118","author":"X Liu","year":"2021","unstructured":"Liu X, Verma A, Garcia G Jr., Ramage H, Lucas A, Myers RL, et al. Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition. Proc Natl Acad Sci U S A. 2021. https:\/\/doi.org\/10.1073\/pnas.2113401118.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1255_CR9","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abm0808","volume":"15","author":"TM Yaron","year":"2022","unstructured":"Yaron TM, Heaton BE, Levy TM, Johnson JL, Jordan TX, Cohen BM, et al. Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication. Sci Signal. 2022;15:eabm0808. https:\/\/doi.org\/10.1126\/scisignal.abm0808.","journal-title":"Sci Signal"},{"key":"1255_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012905","volume":"21","author":"CL Hsieh","year":"2025","unstructured":"Hsieh CL, Chang LY, Chen PJ, Yeh SH. HBV polymerase recruits the phosphatase PP1 to dephosphorylate HBc-Ser170 to complete encapsidation. PLoS Pathog. 2025;21:e1012905. https:\/\/doi.org\/10.1371\/journal.ppat.1012905.","journal-title":"PLoS Pathog"},{"key":"1255_CR11","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.micinf.2010.10.014","volume":"13","author":"YK Cheong","year":"2011","unstructured":"Cheong YK, Ng ML. Dephosphorylation of West Nile virus capsid protein enhances the processes of nucleocapsid assembly. Microbes and infection \/ Institut Pasteur. 2011;13:76\u201384. https:\/\/doi.org\/10.1016\/j.micinf.2010.10.014.","journal-title":"Microbes and infection \/ Institut Pasteur"},{"key":"1255_CR12","doi-asserted-by":"publisher","first-page":"6917","DOI":"10.1128\/JVI.01152-05","volume":"80","author":"LJ Law","year":"2006","unstructured":"Law LJ, Ilkow CS, Tzeng WP, Rawluk M, Stuart DT, Frey TK, et al. Analyses of phosphorylation events in the rubella virus capsid protein: role in early replication events. J Virol. 2006;80:6917\u201325. https:\/\/doi.org\/10.1128\/JVI.01152-05.","journal-title":"J Virol"},{"key":"1255_CR13","doi-asserted-by":"publisher","first-page":"4399","DOI":"10.1038\/s41467-022-32019-3","volume":"13","author":"Z Zhang","year":"2022","unstructured":"Zhang Z, Nomura N, Muramoto Y, Ekimoto T, Uemura T, Liu K, et al. Structure of SARS-CoV-2 membrane protein essential for virus assembly. Nat Commun. 2022;13:4399. https:\/\/doi.org\/10.1038\/s41467-022-32019-3.","journal-title":"Nat Commun"},{"key":"1255_CR14","doi-asserted-by":"publisher","first-page":"4357","DOI":"10.1128\/JVI.03212-15","volume":"90","author":"L Kuo","year":"2016","unstructured":"Kuo L, Hurst-Hess KR, Koetzner CA, Masters PS. Analyses of Coronavirus Assembly Interactions with Interspecies Membrane and Nucleocapsid Protein Chimeras. J Virol. 2016;90:4357\u201368. https:\/\/doi.org\/10.1128\/JVI.03212-15.","journal-title":"J Virol"},{"key":"1255_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20768-y","volume":"12","author":"S Lu","year":"2021","unstructured":"Lu S, Ye Q, Singh D, Cao Y, Diedrich JK, Yates JR 3rd, et al. The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein. Nat Commun. 2021;12:502. https:\/\/doi.org\/10.1038\/s41467-020-20768-y.","journal-title":"Nat Commun"},{"key":"1255_CR16","doi-asserted-by":"publisher","first-page":"2922","DOI":"10.1128\/jvi.77.5.2922-2927.2003","volume":"77","author":"K Narayanan","year":"2003","unstructured":"Narayanan K, Chen CJ, Maeda J, Makino S. Nucleocapsid-independent specific viral RNA packaging via viral envelope protein and viral RNA signal. J Virol. 2003;77:2922\u20137. https:\/\/doi.org\/10.1128\/jvi.77.5.2922-2927.2003.","journal-title":"J Virol"},{"key":"1255_CR17","doi-asserted-by":"publisher","first-page":"6838","DOI":"10.1128\/JVI.72.8.6838-6850.1998","volume":"72","author":"CA de Haan","year":"1998","unstructured":"de Haan CA, Kuo L, Masters PS, Vennema H, Rottier PJ. Coronavirus particle assembly: primary structure requirements of the membrane protein. J Virol. 1998;72:6838\u201350. https:\/\/doi.org\/10.1128\/JVI.72.8.6838-6850.1998.","journal-title":"J Virol"},{"key":"1255_CR18","doi-asserted-by":"publisher","first-page":"9832","DOI":"10.1096\/fj.202001351","volume":"34","author":"SM Cascarina","year":"2020","unstructured":"Cascarina SM, Ross ED. A proposed role for the SARS-CoV-2 nucleocapsid protein in the formation and regulation of biomolecular condensates. FASEB J. 2020;34:9832\u201342. https:\/\/doi.org\/10.1096\/fj.202001351.","journal-title":"FASEB J"},{"key":"1255_CR19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.2217\/fvl-2018-0008","volume":"13","author":"TS Fung","year":"2018","unstructured":"Fung TS, Liu DX. Post-translational modifications of coronavirus proteins: roles and function. Future Virol. 2018;13:405\u201330. https:\/\/doi.org\/10.2217\/fvl-2018-0008.","journal-title":"Future Virol"},{"key":"1255_CR20","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","volume":"583","author":"DE Gordon","year":"2020","unstructured":"Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583:459\u201368. https:\/\/doi.org\/10.1038\/s41586-020-2286-9.","journal-title":"Nature"},{"key":"1255_CR21","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00587-21","volume":"12","author":"YW Cheng","year":"2021","unstructured":"Cheng YW, Chao TL, Li CL, Wang SH, Kao HC, Tsai YM, et al. D614G substitution of SARS-CoV-2 Spike protein increases syncytium formation and virus titer via enhanced Furin-mediated Spike cleavage. MBio. 2021;12:e0058721. https:\/\/doi.org\/10.1128\/mBio.00587-21.","journal-title":"MBio"},{"key":"1255_CR22","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-024-13331-y","volume":"108","author":"TY Chang","year":"2024","unstructured":"Chang TY, Li CJ, Chao TL, Chang SY, Chang SC. Design of the conserved epitope peptide of SARS-CoV-2 spike protein as the broad-spectrum COVID-19 vaccine. Appl Microbiol Biotechnol. 2024;108:486. https:\/\/doi.org\/10.1007\/s00253-024-13331-y.","journal-title":"Appl Microbiol Biotechnol"},{"key":"1255_CR23","doi-asserted-by":"publisher","first-page":"792","DOI":"10.3201\/eid2904.221497","volume":"29","author":"PL Shao","year":"2023","unstructured":"Shao PL, Tu HC, Gong YN, Shu HY, Kirby R, Hsu LY, et al. Emergence and persistent dominance of SARS-CoV-2 Omicron BA.2.3.7 variant, Taiwan. Emerg Infect Dis. 2023;29:792\u20136. https:\/\/doi.org\/10.3201\/eid2904.221497.","journal-title":"Emerg Infect Dis"},{"key":"1255_CR24","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1126\/science.abl6184","volume":"374","author":"AM Syed","year":"2021","unstructured":"Syed AM, Taha TY, Tabata T, Chen IP, Ciling A, Khalid MM, et al. Rapid assessment of SARS-CoV-2-evolved variants using virus-like particles. Science. 2021;374:1626\u201332. https:\/\/doi.org\/10.1126\/science.abl6184.","journal-title":"Science"},{"key":"1255_CR25","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00947","volume":"2","author":"L Ge","year":"2013","unstructured":"Ge L, Melville D, Zhang M, Schekman R. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. Elife. 2013;2:e00947. https:\/\/doi.org\/10.7554\/eLife.00947.","journal-title":"Elife"},{"issue":"3","key":"1255_CR26","doi-asserted-by":"publisher","first-page":"2000045","DOI":"10.2807\/1560-7917.ES.2020.25.3.2000045","volume":"25","author":"VM Corman","year":"2020","unstructured":"Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance. 2020;25(3):2000045.","journal-title":"Eurosurveillance"},{"key":"1255_CR27","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00862","volume":"8","author":"R Xu","year":"2020","unstructured":"Xu R, Shi M, Li J, Song P, Li N. Construction of SARS-CoV-2 virus-like particles by mammalian expression system. Front Bioeng Biotechnol. 2020;8:862. https:\/\/doi.org\/10.3389\/fbioe.2020.00862.","journal-title":"Front Bioeng Biotechnol"},{"key":"1255_CR28","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1385\/1-59745-267-X:23","volume":"365","author":"M Swingle","year":"2007","unstructured":"Swingle M, Ni L, Honkanen RE. Small-molecule inhibitors of ser\/thr protein phosphatases: specificity, use and common forms of abuse. Methods Mol Biol. 2007;365:23\u201338. https:\/\/doi.org\/10.1385\/1-59745-267-X:23.","journal-title":"Methods Mol Biol"},{"key":"1255_CR29","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1146\/annurev.bi.58.070189.002321","volume":"58","author":"P Cohen","year":"1989","unstructured":"Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem. 1989;58:453\u2013508. https:\/\/doi.org\/10.1146\/annurev.bi.58.070189.002321.","journal-title":"Annu Rev Biochem"},{"key":"1255_CR30","doi-asserted-by":"publisher","first-page":"21435","DOI":"10.1016\/S0021-9258(20)88197-6","volume":"264","author":"P Cohen","year":"1989","unstructured":"Cohen P, Cohen PT. Protein phosphatases come of age. J Biol Chem. 1989;264:21435\u20138.","journal-title":"J Biol Chem"},{"key":"1255_CR31","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1080\/15384047.2015.1040961","volume":"16","author":"CS Hong","year":"2015","unstructured":"Hong CS, Ho W, Zhang C, Yang C, Elder JB, Zhuang Z. LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential. Cancer Biol Ther. 2015;16:821\u201333. https:\/\/doi.org\/10.1080\/15384047.2015.1040961.","journal-title":"Cancer Biol Ther"},{"key":"1255_CR32","doi-asserted-by":"publisher","DOI":"10.3390\/life11090957","author":"SH Seok","year":"2021","unstructured":"Seok SH. Structural insights into protein regulation by phosphorylation and substrate recognition of protein kinases\/phosphatases. Life. 2021. https:\/\/doi.org\/10.3390\/life11090957.","journal-title":"Life"},{"key":"1255_CR33","doi-asserted-by":"publisher","first-page":"13848","DOI":"10.1128\/JVI.79.22.13848-13855.2005","volume":"79","author":"PK Hsieh","year":"2005","unstructured":"Hsieh PK, Chang SC, Huang CC, Lee TT, Hsiao CW, Kou YH, et al. Assembly of severe acute respiratory syndrome coronavirus RNA packaging signal into virus-like particles is nucleocapsid dependent. J Virol. 2005;79:13848\u201355. https:\/\/doi.org\/10.1128\/JVI.79.22.13848-13855.2005.","journal-title":"J Virol"},{"key":"1255_CR34","doi-asserted-by":"publisher","first-page":"6144","DOI":"10.1074\/jbc.275.9.6144","volume":"275","author":"RI Ludowyke","year":"2000","unstructured":"Ludowyke RI, Holst J, Mudge LM, Sim AT. Transient translocation and activation of protein phosphatase 2A during mast cell secretion. J Biol Chem. 2000;275:6144\u201352. https:\/\/doi.org\/10.1074\/jbc.275.9.6144.","journal-title":"J Biol Chem"},{"key":"1255_CR35","doi-asserted-by":"publisher","first-page":"5322","DOI":"10.1074\/jbc.M108623200","volume":"277","author":"RT Boudreau","year":"2002","unstructured":"Boudreau RT, Garduno R, Lin TJ. Protein phosphatase 2A and protein kinase Calpha are physically associated and are involved in Pseudomonas aeruginosa-induced interleukin 6 production by mast cells. J Biol Chem. 2002;277:5322\u20139. https:\/\/doi.org\/10.1074\/jbc.M108623200.","journal-title":"J Biol Chem"},{"key":"1255_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19619-7","volume":"11","author":"S Klein","year":"2020","unstructured":"Klein S, Cortese M, Winter SL, Wachsmuth-Melm M, Neufeldt CJ, Cerikan B, et al. SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat Commun. 2020;11:5885. https:\/\/doi.org\/10.1038\/s41467-020-19619-7.","journal-title":"Nat Commun"},{"issue":"1","key":"1255_CR37","doi-asserted-by":"publisher","first-page":"7970","DOI":"10.1038\/s41467-025-62922-4","volume":"16","author":"B Favetta","year":"2025","unstructured":"Favetta B, Wang H, Cubuk J, Singh A, Barai M, Ramirez C, et al. Phosphorylation Toggles the SARS-CoV-2 Nucleocapsid Protein Between Two Membrane-Associated Condensate States. Nat Commun. 2025;16(1):7970.","journal-title":"Nat Commun"},{"key":"1255_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2024.103253","volume":"5","author":"JA Weesner","year":"2024","unstructured":"Weesner JA, van de Vlekkert D, Fremuth LE, d\u2019Azzo A. Protocol for the isolation and purification of endoplasmic reticulum-plasma membrane junctions from the mouse brain. STAR Protoc. 2024;5:103253. https:\/\/doi.org\/10.1016\/j.xpro.2024.103253.","journal-title":"STAR Protoc"},{"key":"1255_CR39","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1016\/j.molcel.2020.11.025","volume":"80","author":"CR Carlson","year":"2020","unstructured":"Carlson CR, Asfaha JB, Ghent CM, Howard CJ, Hartooni N, Safari M, et al. Phosphoregulation of phase separation by the SARS-CoV-2 N protein suggests a biophysical basis for its dual functions. Mol Cell. 2020;80:1092-1103 e1094. https:\/\/doi.org\/10.1016\/j.molcel.2020.11.025.","journal-title":"Mol Cell"},{"key":"1255_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w","author":"J Abramson","year":"2024","unstructured":"Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature. 2024. https:\/\/doi.org\/10.1038\/s41586-024-07487-w.","journal-title":"Nature"},{"key":"1255_CR41","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26842","author":"S Loonen","year":"2025","unstructured":"Loonen S, van Steenis L, Bauer M, Sostaric N. Phosphorylation changes SARS-CoV-2 nucleocapsid protein\u2019s structural dynamics and its interaction with RNA. Proteins. 2025. https:\/\/doi.org\/10.1002\/prot.26842.","journal-title":"Proteins"},{"key":"1255_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103255","volume":"65","author":"M Hoffmann","year":"2021","unstructured":"Hoffmann M, Hofmann-Winkler H, Smith JC, Kruger N, Arora P, Sorensen LK, et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 2021;65:103255. https:\/\/doi.org\/10.1016\/j.ebiom.2021.103255.","journal-title":"EBioMedicine"},{"key":"1255_CR43","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.neurobiolaging.2014.07.035","volume":"36","author":"Y Wang","year":"2015","unstructured":"Wang Y, Yang R, Gu J, Yin X, Jin N, Xie S, et al. Cross talk between PI3K-AKT-GSK-3beta and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging. 2015;36:188\u2013200. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2014.07.035.","journal-title":"Neurobiol Aging"},{"key":"1255_CR44","doi-asserted-by":"publisher","first-page":"4521","DOI":"10.1128\/JVI.02365-07","volume":"82","author":"Y Yu","year":"2008","unstructured":"Yu Y, Alwine JC. Interaction between simian virus 40 large T antigen and insulin receptor substrate 1 is disrupted by the K1 mutation, resulting in the loss of large T antigen-mediated phosphorylation of Akt. J Virol. 2008;82:4521\u20136. https:\/\/doi.org\/10.1128\/JVI.02365-07.","journal-title":"J Virol"},{"key":"1255_CR45","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2282","volume":"32","author":"MM Kesheh","year":"2022","unstructured":"Kesheh MM, Hosseini P, Soltani S, Zandi M. An overview on the seven pathogenic human coronaviruses. Rev Med Virol. 2022;32:e2282. https:\/\/doi.org\/10.1002\/rmv.2282.","journal-title":"Rev Med Virol"},{"key":"1255_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s44298-025-00152-7","volume":"3","author":"Y Bruggemann","year":"2025","unstructured":"Bruggemann Y, Meister TL, Heinen N, Richter E, Westhoven S, Poppe M, et al. JNK kinase regulates phosphorylation of HCoV-229E nucleocapsid protein. Npj Viruses. 2025;3:69. https:\/\/doi.org\/10.1038\/s44298-025-00152-7.","journal-title":"Npj Viruses"},{"key":"1255_CR47","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.cell.2020.12.006","volume":"184","author":"WM Schneider","year":"2021","unstructured":"Schneider WM, Luna JM, Hoffmann HH, Sanchez-Rivera FJ, Leal AA, Ashbrook AW, et al. Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks. Cell. 2021;184:120-132 e114. https:\/\/doi.org\/10.1016\/j.cell.2020.12.006.","journal-title":"Cell"},{"key":"1255_CR48","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.cell.2006.09.025","volume":"127","author":"Y Xing","year":"2006","unstructured":"Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, et al. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell. 2006;127:341\u201353. https:\/\/doi.org\/10.1016\/j.cell.2006.09.025.","journal-title":"Cell"},{"key":"1255_CR49","doi-asserted-by":"publisher","first-page":"7556","DOI":"10.1128\/JVI.67.12.7556-7560.1993","volume":"67","author":"T Kleinberger","year":"1993","unstructured":"Kleinberger T, Shenk T. Adenovirus E4orf4 protein binds to protein phosphatase 2A, and the complex down regulates E1A-enhanced junB transcription. J Virol. 1993;67:7556\u201360. https:\/\/doi.org\/10.1128\/JVI.67.12.7556-7560.1993.","journal-title":"J Virol"},{"key":"1255_CR50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013760","volume":"5","author":"AN Godet","year":"2010","unstructured":"Godet AN, Guergnon J, Croset A, Cayla X, Falanga PB, Colle JH, et al. PP2A1 binding, cell transducing and apoptotic properties of Vpr(77-92): a new functional domain of HIV-1 Vpr proteins. PLoS ONE. 2010;5:e13760. https:\/\/doi.org\/10.1371\/journal.pone.0013760.","journal-title":"PLoS ONE"},{"key":"1255_CR51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010627","volume":"18","author":"BA Johnson","year":"2022","unstructured":"Johnson BA, Zhou Y, Lokugamage KG, Vu MN, Bopp N, Crocquet-Valdes PA, et al. Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis. PLoS Pathog. 2022;18:e1010627. https:\/\/doi.org\/10.1371\/journal.ppat.1010627.","journal-title":"PLoS Pathog"},{"key":"1255_CR52","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1007\/s10637-015-0278-7","volume":"33","author":"JE Gray","year":"2015","unstructured":"Gray JE, Infante JR, Brail LH, Simon GR, Cooksey JF, Jones SF, et al. A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest New Drugs. 2015;33:1187\u201396. https:\/\/doi.org\/10.1007\/s10637-015-0278-7.","journal-title":"Invest New Drugs"},{"key":"1255_CR53","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.3109\/10428194.2015.1122781","volume":"57","author":"DA Rizzieri","year":"2016","unstructured":"Rizzieri DA, Cooley S, Odenike O, Moonan L, Chow KH, Jackson K, et al. An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. Leuk Lymphoma. 2016;57:1800\u20136. https:\/\/doi.org\/10.3109\/10428194.2015.1122781.","journal-title":"Leuk Lymphoma"},{"key":"1255_CR54","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/j.1600-0447.1995.tb09545.x","volume":"92","author":"HV Jensen","year":"1995","unstructured":"Jensen HV, Plenge P, Mellerup ET, Davidsen K, Toftegaard L, Aggernaes H, et al. Lithium prophylaxis of manic-depressive disorder: daily lithium dosing schedule versus every second day. Acta Psychiatr Scand. 1995;92:69\u201374. https:\/\/doi.org\/10.1111\/j.1600-0447.1995.tb09545.x.","journal-title":"Acta Psychiatr Scand"},{"key":"1255_CR55","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1080\/22221751.2020.1799723","volume":"9","author":"S Appelberg","year":"2020","unstructured":"Appelberg S, Gupta S, Svensson Akusjarvi S, Ambikan AT, Mikaeloff F, Saccon E, et al. Dysregulation in Akt\/mTOR\/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect. 2020;9:1748\u201360. https:\/\/doi.org\/10.1080\/22221751.2020.1799723.","journal-title":"Emerg Microbes Infect"},{"key":"1255_CR56","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.7150\/ijbs.57810","volume":"17","author":"F Sun","year":"2021","unstructured":"Sun F, Mu C, Kwok HF, Xu J, Wu Y, Liu W, et al. Capivasertib restricts SARS-CoV-2 cellular entry: a potential clinical application for COVID-19. Int J Biol Sci. 2021;17:2348\u201355. https:\/\/doi.org\/10.7150\/ijbs.57810.","journal-title":"Int J Biol Sci"},{"key":"1255_CR57","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.1158\/1078-0432.CCR-16-2299","volume":"23","author":"V Chung","year":"2017","unstructured":"Chung V, Mansfield AS, Braiteh F, Richards D, Durivage H, Ungerleider RS, et al. Safety, tolerability, and preliminary activity of LB-100, an inhibitor of protein phosphatase 2A, in patients with relapsed solid tumors: An open-label, dose escalation, first-in-human, Phase I trial. Clin Cancer Res. 2017;23:3277\u201384. https:\/\/doi.org\/10.1158\/1078-0432.CCR-16-2299.","journal-title":"Clin Cancer Res"}],"container-title":["Journal of Biomedical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12929-026-01255-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12929-026-01255-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12929-026-01255-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T13:51:05Z","timestamp":1778853065000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12929-026-01255-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1255"],"URL":"https:\/\/doi.org\/10.1186\/s12929-026-01255-w","relation":{},"ISSN":["1423-0127"],"issn-type":[{"value":"1423-0127","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]},"assertion":[{"value":"20 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This article does not contain any studies with human or animal subjects performed by any of the authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"51"}}