{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T02:39:43Z","timestamp":1769827183145,"version":"3.49.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["75N93019C00010"],"award-info":[{"award-number":["75N93019C00010"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>High yield production of recombinant HIV SOSIP envelope (Env) trimers has proven elusive as numerous disulfide bonds, proteolytic cleavage and extensive glycosylation pose high demands on the host cell machinery and stress imposed by accumulation of misfolded proteins may ultimately lead to cellular toxicity. The present study utilized the <jats:italic>Nicotiana benthamiana\/p19 (N.b.\/p19<\/jats:italic>) transient plant system to assess co-expression of two ER master regulators and 5 chaperones, crucial in the folding process, to enhance yields of three Env SOSIPs, single chain <jats:italic>BG505 SOSIP.664 gp140, CH505TF.6R.SOSIP.664.v4.1<\/jats:italic> and <jats:italic>CH848-10.17-DT9<\/jats:italic>. Phenotypic changes in leaves induced by SOSIP expression were employed to rapidly identify chaperone-assisted improvement in health and expression. Up to 15-fold increases were obtained by co-infiltration of peptidylprolvl isomerase (PPI) and calreticulin (CRT) which were further enhanced by addition of the ER-retrieval KDEL tags to the SOSIP genes; levels depending on individual SOSIP type, day of harvest and chaperone gene dosage. Results are consistent with reducing SOSIP misfolding and cellular stress due to increased exposure to the plant host cell\u2019s calnexin\/calreticulin network and accelerating the rate-limiting cis\u2013trans isomerization of Xaa-Pro peptide bonds respectively. Plant transient co-expression facilitates rapid identification of host cell factors and will be translatable to other complex glycoproteins and mammalian expression systems.<\/jats:p>","DOI":"10.1038\/s41598-022-14075-3","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T18:03:16Z","timestamp":1655316196000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Enhanced HIV SOSIP Envelope yields in plants through transient co-expression of peptidyl-prolyl isomerase B and calreticulin chaperones and ER targeting"],"prefix":"10.1038","volume":"12","author":[{"given":"Yvonne J.","family":"Rosenberg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoming","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan P.","family":"Lees","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lori A.","family":"Urban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingjun","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Sack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"14075_CR1","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1038\/458584a","volume":"458","author":"JF Scheid","year":"2009","unstructured":"Scheid, J. F. et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636\u2013640. https:\/\/doi.org\/10.1038\/458584a (2009).","journal-title":"Nature"},{"key":"14075_CR2","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1126\/science.1178746","volume":"326","author":"LM Walker","year":"2009","unstructured":"Walker, L. M. et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285\u2013289. https:\/\/doi.org\/10.1126\/science.1178746 (2009).","journal-title":"Science"},{"issue":"46","key":"14075_CR3","doi-asserted-by":"publisher","first-page":"18921","DOI":"10.1073\/pnas.121478510","volume":"109","author":"B Moldt","year":"2012","unstructured":"Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. USA 109(46), 18921\u201318925. https:\/\/doi.org\/10.1073\/pnas.121478510 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"14075_CR4","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/nm.1974","volume":"15","author":"AJ Hessell","year":"2009","unstructured":"Hessell, A. J. et al. Effective low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat. Med. 15, 951\u2013954. https:\/\/doi.org\/10.1038\/nm.1974 (2009).","journal-title":"Nat. Med."},{"key":"14075_CR5","doi-asserted-by":"publisher","first-page":"e0152760","DOI":"10.1371\/journal.pone.0152760","volume":"11","author":"YJ Rosenberg","year":"2016","unstructured":"Rosenberg, Y. J. et al. Protection against SHIV challenge by subcutaneous administration of the plant-derived PGT121 broadly neutralizing antibody in Macaques. PLoS ONE 11, e0152760. https:\/\/doi.org\/10.1371\/journal.pone.0152760 (2016).","journal-title":"PLoS ONE"},{"key":"14075_CR6","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/nature12744","volume":"1503","author":"DH Barouch","year":"2013","unstructured":"Barouch, D. H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 1503, 224\u2013228. https:\/\/doi.org\/10.1038\/nature12744 (2013).","journal-title":"Nature"},{"issue":"7427","key":"14075_CR7","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/nature11604","volume":"492","author":"F Klein","year":"2012","unstructured":"Klein, F. et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492(7427), 118\u2013122. https:\/\/doi.org\/10.1038\/nature11604 (2012).","journal-title":"Nature"},{"key":"14075_CR8","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/nature14411","volume":"522","author":"M Caskey","year":"2015","unstructured":"Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487\u2013491. https:\/\/doi.org\/10.1038\/nature14411 (2015).","journal-title":"Nature"},{"key":"14075_CR9","doi-asserted-by":"publisher","first-page":"D1133","DOI":"10.1093\/nar\/gkt1083","volume":"42","author":"AM Eroshkin","year":"2014","unstructured":"Eroshkin, A. M. et al. bNAber: Database of broadly neutralizing HIV antibodies. Nucleic Acid Res. 42, D1133\u2013D1139 (2014).","journal-title":"Nucleic Acid Res."},{"key":"14075_CR10","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1146\/annurev-immunol-041015-055515","volume":"34","author":"DR Burton","year":"2016","unstructured":"Burton, D. R. & Hangartner, L. Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu. Rev. Immunol. 34, 635\u2013659. https:\/\/doi.org\/10.1146\/annurev-immunol-041015-055515 (2016).","journal-title":"Annu. Rev. Immunol."},{"key":"14075_CR11","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1146\/annurev-med-110118-045506","volume":"71","author":"ST Karuna","year":"2020","unstructured":"Karuna, S. T. & Lawrence Corey, L. Broadly neutralizing antibodies for HIV prevention. Annu. Rev. Med. 71, 329\u2013346. https:\/\/doi.org\/10.1146\/annurev-med-110118-045506 (2020).","journal-title":"Annu. Rev. Med."},{"issue":"6165","key":"14075_CR12","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1126\/science.1245625","volume":"342","author":"JP Julian","year":"2013","unstructured":"Julian, J. P. et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science. 342(6165), 1477\u201383. https:\/\/doi.org\/10.1126\/science.1245625 (2013).","journal-title":"Science."},{"key":"14075_CR13","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.immuni.2019.10.008","volume":"51","author":"V Dubrovskaya","year":"2019","unstructured":"Dubrovskaya, V. et al. Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability. Immunity. 51, 915\u2013929. https:\/\/doi.org\/10.1016\/j.immuni.2019.10.008 (2019).","journal-title":"Immunity."},{"issue":"10","key":"14075_CR14","doi-asserted-by":"publisher","first-page":"5318","DOI":"10.1128\/JVI.03451-14","volume":"89","author":"IS Georgiev","year":"2015","unstructured":"Georgiev, I. S. et al. Single-chain soluble BG505 SOSIP gp140 trimers as structural and antigenic mimics of mature closed HIV-1 Env. J. Virol. 89(10), 5318\u20135329. https:\/\/doi.org\/10.1128\/JVI.03451-14 (2015).","journal-title":"J. Virol."},{"key":"14075_CR15","doi-asserted-by":"publisher","first-page":"e1003618","DOI":"10.1371\/journal.ppat.1003618","volume":"9","author":"RW Sanders","year":"2013","unstructured":"Sanders, R. W. et al. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 9, e1003618. https:\/\/doi.org\/10.1371\/journal.ppat.1003618 (2013).","journal-title":"PLoS Pathog."},{"issue":"4","key":"14075_CR16","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1002\/bit.26498","volume":"115","author":"AK Dey","year":"2018","unstructured":"Dey, A. K. et al. cGMP production and analysis of BG505 SOSIP.664, an extensively glycosylated, trimeric HIV-1 envelope glycoprotein vaccine candidate. Biotechnol. Bioeng. 115(4), 885\u2013899. https:\/\/doi.org\/10.1002\/bit.26498 (2018).","journal-title":"Biotechnol. Bioeng."},{"issue":"13","key":"14075_CR17","doi-asserted-by":"publisher","first-page":"3681","DOI":"10.1016\/j.celrep.2017.12.028","volume":"21","author":"KO Saunders","year":"2017","unstructured":"Saunders, K. O. et al. Vaccine induction of heterologous tier 2 HIV-1 neutralizing antibodies in animal models. Cell Rep. 21(13), 3681\u20133690. https:\/\/doi.org\/10.1016\/j.celrep.2017.12.028 (2017).","journal-title":"Cell Rep."},{"key":"14075_CR18","doi-asserted-by":"publisher","first-page":"e01957","DOI":"10.1128\/JVI.01957-17","volume":"92","author":"A Torrents de la Pe\u00f1a","year":"2018","unstructured":"Torrents de la Pe\u00f1a, A. et al. Immunogenicity in rabbits of HIV-1 SOSIP trimers from clades A, B, and C, given individually, sequentially, or in combination. J. Virol. 92, e01957. https:\/\/doi.org\/10.1128\/JVI.01957-17 (2018).","journal-title":"J. Virol."},{"key":"14075_CR19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01116","author":"S Bale","year":"2018","unstructured":"Bale, S. et al. Cleavage-independent HIV-1 trimers from CHO cell lines elicit robust autologous tier 2 neutralizing antibodies. Front. Immunol. https:\/\/doi.org\/10.3389\/fimmu.2018.01116 (2018).","journal-title":"Front. Immunol."},{"issue":"24","key":"14075_CR20","doi-asserted-by":"publisher","first-page":"e01214-20","DOI":"10.1128\/JVI.01214-20","volume":"94","author":"A Schorcht","year":"2020","unstructured":"Schorcht, A. et al. Neutralizing antibody responses induced by HIV-1 envelope glyco protein SOSIP trimers derived from elite neutralizers. J Virol. 94(24), e01214-20. https:\/\/doi.org\/10.1128\/JVI.01214-20 (2020).","journal-title":"J Virol."},{"key":"14075_CR21","doi-asserted-by":"publisher","first-page":"e00862","DOI":"10.1128\/JVI","volume":"91","author":"JT Sullivan","year":"2017","unstructured":"Sullivan, J. T. et al. High-throughput protein engineering improves the antigenicity and stability of soluble HIV-1 envelope glycoprotein SOSIP trimers. J. Virol. 91, e00862-17. https:\/\/doi.org\/10.1128\/JVI (2017).","journal-title":"J. Virol."},{"issue":"1","key":"14075_CR22","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.immuni.2018.11.011","volume":"50","author":"MG Pauthner","year":"2019","unstructured":"Pauthner, M. G. et al. Vaccine-induced protection from homologous Tier 2 SHIV challenge in nonhuman primates depends on serum-neutralizing antibody titers. Immunity 50(1), 241-252.e6. https:\/\/doi.org\/10.1016\/j.immuni.2018.11.011 (2019).","journal-title":"Immunity"},{"key":"14075_CR23","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1146\/annurev-arplant-050213-035850","volume":"65","author":"E Stoger","year":"2014","unstructured":"Stoger, E., Fischer, R., Moloney, M. & Ma, J. K. Plant molecular pharming for the treatment of chronic and infectious diseases. Annu. Rev. Plant Biol. 65, 743\u2013768. https:\/\/doi.org\/10.1146\/annurev-arplant-050213-035850 (2014).","journal-title":"Annu. Rev. Plant Biol."},{"key":"14075_CR24","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.copbio.2014.12.008","volume":"32","author":"M Sack","year":"2015","unstructured":"Sack, M., Hofbauer, A., Fischer, R. & Stoger, E. The increasing value of plant-made proteins. Curr. Opin. Biotechnol. 32, 163\u2013170. https:\/\/doi.org\/10.1016\/j.copbio.2014.12.008 (2015).","journal-title":"Curr. Opin. Biotechnol."},{"key":"14075_CR25","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1016\/j.biotechadv","volume":"33","author":"JF Buyel","year":"2015","unstructured":"Buyel, J. F., Twyman, R. M. & Fischer, R. Extraction and downstream processing of plant-derived recombinant proteins. Biotechnol. Adv. 33, 902\u201313. https:\/\/doi.org\/10.1016\/j.biotechadv (2015).","journal-title":"Biotechnol. Adv."},{"issue":"3","key":"14075_CR26","doi-asserted-by":"publisher","first-page":"e58724","DOI":"10.1371\/journal.pone.0058724","volume":"28","author":"YJ Rosenberg","year":"2013","unstructured":"Rosenberg, Y. J. et al. Rapid high-level production of functional HIV broadly neutralizing monoclonal antibodies in transient plant expression systems. PLoS ONE 28(3), e58724. https:\/\/doi.org\/10.1371\/journal.pone.0058724 (2013).","journal-title":"PLoS ONE"},{"key":"14075_CR27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.3389\/fpls.2016.00159","volume":"7","author":"S Menzel","year":"2016","unstructured":"Menzel, S. et al. Optimized blanching reduces the host cell protein content and substantially enhances the recovery and stability of two plant-derived malaria vaccine candidates. Front. Plant Sci. 7, 159. https:\/\/doi.org\/10.3389\/fpls.2016.00159 (2016).","journal-title":"Front. Plant Sci."},{"key":"14075_CR28","doi-asserted-by":"publisher","first-page":"13247","DOI":"10.1038\/srep13247","volume":"5","author":"YJ Rosenberg","year":"2015","unstructured":"Rosenberg, Y. J. et al. A highly stable minimally processed plant-derived recombinant acetylcholinesterase for nerve agent detection in adverse conditions. Sci. Rep. 5, 13247. https:\/\/doi.org\/10.1038\/srep13247 (2015).","journal-title":"Sci. Rep."},{"issue":"15","key":"14075_CR29","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1056\/NEJMoa1604330","volume":"375","author":"The PREVAIL II Writing Group, for the Multi-National PREVAIL II Study Team","year":"2016","unstructured":"The PREVAIL II Writing Group, for the Multi-National PREVAIL II Study Team. A randomized, controlled trial of ZMapp for Ebola virus infection. N. Engl. J. Med. 375(15), 1448\u20131456. https:\/\/doi.org\/10.1056\/NEJMoa1604330 (2016).","journal-title":"N. Engl. J. Med."},{"key":"14075_CR30","doi-asserted-by":"publisher","first-page":"547","DOI":"10.3329\/jhpn.v29i6.9889","volume":"29","author":"AM Laffan","year":"2011","unstructured":"Laffan, A. M. et al. Lactoferrin for the prevention of post-antibiotic diarrhoea. J. Health Popul. Nutr. 29, 547\u2013551. https:\/\/doi.org\/10.3329\/jhpn.v29i6.9889 (2011).","journal-title":"J. Health Popul. Nutr."},{"key":"14075_CR31","unstructured":"Taylor, N. P. For FierceBiotech. Medicago, GSK Post Positive Midphase Data on Plant-Derived COVID-19 Vaccine. https:\/\/fiercebiotech.com\/biotech\/medicago-gsk-post-positive-midphase-data-plant-derived-covid-19-vaccine (2021)"},{"key":"14075_CR32","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1016\/j.celrep.2016.02.058","volume":"14","author":"A-J Behrens","year":"2016","unstructured":"Behrens, A.-J. et al. Composition and antigenic effects of individual glycan sites of a trimeric HIV-1 envelope glycoprotein. Cell Rep. 14, 2695\u2013706. https:\/\/doi.org\/10.1016\/j.celrep.2016.02.058 (2016).","journal-title":"Cell Rep."},{"key":"14075_CR33","doi-asserted-by":"publisher","first-page":"e012428-16","DOI":"10.1128\/JVI.02428-16","volume":"91","author":"EP Go","year":"2017","unstructured":"Go, E. P. et al. Glycosylation benchmark profile for HIV-1 envelope glycoprotein production based on eleven Env trimers. J. Virol. 91, e012428-16. https:\/\/doi.org\/10.1128\/JVI.02428-16 (2017).","journal-title":"J. Virol."},{"key":"14075_CR34","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.3389\/fpls.2019.01378","volume":"10","author":"E Margolin","year":"2019","unstructured":"Margolin, E. et al. Production and immunogenicity of soluble plant-produced HIV-1 subtype C envelope gp140 immunogens. Front Plant Sci. 10, 1378. https:\/\/doi.org\/10.3389\/fpls.2019.01378 (2019).","journal-title":"Front Plant Sci."},{"key":"14075_CR35","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1111\/pbi.13369","volume":"18","author":"E Margolin","year":"2020","unstructured":"Margolin, E. et al. Co- expression of human calreticulin significantly improves the production of HIV gp140 and other viral glycoproteins in plants. Plant Biotechnol. J. 18, 2109\u201317. https:\/\/doi.org\/10.1111\/pbi.13369 (2020).","journal-title":"Plant Biotechnol. J."},{"key":"14075_CR36","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/s12985-015-0436-8","volume":"12","author":"FF Pera","year":"2015","unstructured":"Pera, F. F. et al. Engineering and expression of a human rotavirus candidate vaccine in Nicotiana benthamiana. Virol. J. 12, 205. https:\/\/doi.org\/10.1186\/s12985-015-0436-8 (2015).","journal-title":"Virol. J."},{"key":"14075_CR37","doi-asserted-by":"publisher","first-page":"8003","DOI":"10.1038\/srep08003","volume":"5","author":"KT Hamorsky","year":"2015","unstructured":"Hamorsky, K. T. et al. N-glycosylation of cholera toxin B subunit in Nicotiana benthamiana: Impacts on host stress response, production yield and vaccine potential. Sci. Rep. 5, 8003. https:\/\/doi.org\/10.1038\/srep08003 (2015).","journal-title":"Sci. Rep."},{"key":"14075_CR38","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.tcb.2016.12.002","volume":"27","author":"L Qi","year":"2017","unstructured":"Qi, L., Tsai, B. & Arvan, P. New Insights into the physiological role of endoplasmic reticulum-associated degradation. Rev. Spec. Ser. Mitochondria. 27, 430\u2013440. https:\/\/doi.org\/10.1016\/j.tcb.2016.12.002 (2017).","journal-title":"Rev. Spec. Ser. Mitochondria."},{"issue":"4","key":"14075_CR39","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1111\/tpj.13449","volume":"90","author":"E Angelos","year":"2017","unstructured":"Angelos, E., Ruberti, C., Kim, S.-J. & Brandizzi, F. Maintaining the factory: The roles of the unfolded protein response in cellular homeostasis in plants. Plant J. 90(4), 671\u2013682. https:\/\/doi.org\/10.1111\/tpj.13449 (2017).","journal-title":"Plant J."},{"key":"14075_CR40","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12985-015-0298-0","volume":"12","author":"M Borsa","year":"2015","unstructured":"Borsa, M. et al. HIV infection and antiretroviral therapy lead to unfolded protein respo. Virol. J. 12, 77. https:\/\/doi.org\/10.1186\/s12985-015-0298-0 (2015).","journal-title":"Virol. J."},{"key":"14075_CR41","doi-asserted-by":"publisher","first-page":"18929","DOI":"10.1038\/srep18929","volume":"6","author":"A Shah","year":"2016","unstructured":"Shah, A., Vaidya, N. K., Bhat, H. K. & Kumar, A. HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1\u03b1, JNK and AP-1 pathway. Sci. Rep. 6, 18929. https:\/\/doi.org\/10.1038\/srep18929 (2016).","journal-title":"Sci. Rep."},{"key":"14075_CR42","doi-asserted-by":"publisher","DOI":"10.3389\/fpls.2012.00293","author":"L Zhang","year":"2012","unstructured":"Zhang, L. & Wang, A. Virus-induced ER stress and the unfolded protein response. Front. Plant Sci. https:\/\/doi.org\/10.3389\/fpls.2012.00293 (2012).","journal-title":"Front. Plant Sci."},{"issue":"2","key":"14075_CR43","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1104\/pp.111.174110","volume":"156","author":"C Ye","year":"2011","unstructured":"Ye, C., Dickman, M. B., Whitham, S. A., Payton, M. & Verchot, J. The unfolded protein response is triggered by a plant viral movement protein. Plant Physiol. 156(2), 741\u2013755. https:\/\/doi.org\/10.1104\/pp.111.174110 (2011).","journal-title":"Plant Physiol."},{"key":"14075_CR44","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1111\/tra.12358","volume":"17","author":"L Lamriben","year":"2016","unstructured":"Lamriben, L., Graham, J. B., Adams, B. M. & Hebert, D. N. N-glycan-based ER molecular chaperone and protein quality control system: The calnexin binding cycle. Traffic 17, 308\u2013326. https:\/\/doi.org\/10.1111\/tra.12358 (2016).","journal-title":"Traffic"},{"key":"14075_CR45","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1242\/dmm.014589","volume":"7","author":"SP Ferris","year":"2014","unstructured":"Ferris, S. P., Kodali, V. K. & Kaufman, R. J. Glycoprotein folding and quality-control mechanisms protein-folding diseases. Dis. Model Mech. 7, 331\u2013341. https:\/\/doi.org\/10.1242\/dmm.014589 (2014).","journal-title":"Dis. Model Mech."},{"issue":"3","key":"14075_CR46","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a013169(2013)","volume":"5","author":"BM Gardner","year":"2013","unstructured":"Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. & Walter, P. Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol. 5(3), a01169. https:\/\/doi.org\/10.1101\/cshperspect.a013169(2013) (2013).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"issue":"4","key":"14075_CR47","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1021\/pr4012602","volume":"13","author":"NA Haverland","year":"2014","unstructured":"Haverland, N. A., Fox, H. S. & Ciborowski, P. Quantitative proteomics by SWATH-MS reveals altered expression of nucleic acid binding and regulatory proteins in HIV-1-infected macro- phages. J. Proteome Res. 13(4), 2109\u201319. https:\/\/doi.org\/10.1021\/pr4012602 (2014).","journal-title":"J. Proteome Res."},{"issue":"5","key":"14075_CR48","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.jmb.2004.10.091","volume":"345","author":"C Scholz","year":"2005","unstructured":"Scholz, C. et al. Functional solubilization of aggregation-prone HIV envelope proteins by covalent fusion with chaperone modules. J. Mol. Biol. 345(5), 1229\u20131241. https:\/\/doi.org\/10.1016\/j.jmb.2004.10.091 (2005).","journal-title":"J. Mol. Biol."},{"issue":"6","key":"14075_CR49","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1074\/jbc.REV118.002804","volume":"294","author":"KFR Pobre","year":"2019","unstructured":"Pobre, K. F. R., Poet, G. J. & Hendershot, L. M. The endoplasmic reticulum (ER) chaperone BiP is a master regulator of ER functions: Getting by with a little help from ERdj friends. J. Biol. Chem. 294(6), 2098\u20132108. https:\/\/doi.org\/10.1074\/jbc.REV118.002804 (2019).","journal-title":"J. Biol. Chem."},{"key":"14075_CR50","doi-asserted-by":"publisher","first-page":"e26067","DOI":"10.7554\/eLife.26067","volume":"6","author":"EL Snapp","year":"2017","unstructured":"Snapp, E. L. et al. Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide. Elife. 6, e26067. https:\/\/doi.org\/10.7554\/eLife.26067 (2017).","journal-title":"Elife."},{"key":"14075_CR51","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/nature12053","volume":"496","author":"H-X Liao","year":"2013","unstructured":"Liao, H.-X. et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469\u201376. https:\/\/doi.org\/10.1038\/nature12053 (2013).","journal-title":"Nature"},{"key":"14075_CR52","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay7199","author":"KO Saunders","year":"2019","unstructured":"Saunders, K. O. et al. Targeted selection of HIV-specific antibody mutations by engineering B cell maturation. Science https:\/\/doi.org\/10.1126\/science.aay7199 (2019).","journal-title":"Science"},{"issue":"4","key":"14075_CR53","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.immuni.2017.03.017","volume":"46","author":"JH Lee","year":"2017","unstructured":"Lee, J. H. et al. A broadly neutralizing antibody targets the dynamic HIV envelope trimer apex via a long, rigidified, and anionic \u03b2-hairpin structure. Immunity 46(4), 690\u2013702. https:\/\/doi.org\/10.1016\/j.immuni.2017.03.017 (2017).","journal-title":"Immunity"},{"key":"14075_CR54","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1111\/j.1742-4658.2007.05639.x","volume":"274","author":"H Yoshida","year":"2007","unstructured":"Yoshida, H. ER stress and diseases. FEBS J. 274, 630\u2013658. https:\/\/doi.org\/10.1111\/j.1742-4658.2007.05639.x (2007).","journal-title":"FEBS J."},{"issue":"4","key":"14075_CR55","first-page":"429","volume":"38","author":"M Xu","year":"1995","unstructured":"Xu, M., Meng, W. & Ma, X. PDI-, PPI- and chaperone-catalyzed refolding of recombinant human IL-2 and GM-CSF. Sci. China B. 38(4), 429\u2013437 (1995).","journal-title":"Sci. China B."},{"issue":"9","key":"14075_CR56","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1002\/pro.5560020913","volume":"2","author":"H Lilie","year":"1993","unstructured":"Lilie, H., Lang, K., Rudolph, R. & Buchner, J. Prolyl isomerases catalyze antibody folding in vitro. Protein Sci. 2(9), 1490\u20136. https:\/\/doi.org\/10.1002\/pro.5560020913 (1993).","journal-title":"Protein Sci."},{"issue":"3","key":"14075_CR57","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1007\/s00726-011-1211-9","volume":"43","author":"AP Joseph","year":"2012","unstructured":"Joseph, A. P., Srinivasan, N., Alexandre, G. & Brevern, D. E. Cis-trans peptide variations in structurally similar proteins. Amino Acids 43(3), 1369\u201381. https:\/\/doi.org\/10.1007\/s00726-011-1211-9 (2012).","journal-title":"Amino Acids"},{"key":"14075_CR58","doi-asserted-by":"publisher","first-page":"e0213438","DOI":"10.1371\/journal.pone.0213438","volume":"14","author":"T Mamedov","year":"2019","unstructured":"Mamedov, T. et al. Engineering, and production of functionally active human Furin in N. benthamiana plant: In vivo post-translational processing of target proteins by Furin in plants. PLoS ONE 14, e0213438. https:\/\/doi.org\/10.1371\/journal.pone.0213438 (2019).","journal-title":"PLoS ONE"},{"issue":"9","key":"14075_CR59","doi-asserted-by":"publisher","first-page":"e024286","DOI":"10.1128\/JVI.02428-16","volume":"91","author":"EP Go","year":"2017","unstructured":"Go, E. P. et al. Glycosylation benchmark profile for HIV-1 envelope glycoprotein production based on eleven Env trimers. J. Virol. 91(9), e024286. https:\/\/doi.org\/10.1128\/JVI.02428-16 (2017).","journal-title":"J. Virol."},{"key":"14075_CR60","doi-asserted-by":"publisher","first-page":"3693","DOI":"10.1038\/s41467-018-06121-4","volume":"9","author":"L Cao","year":"2018","unstructured":"Cao, L. et al. Differential processing of HIV envelope glycans on the virus and soluble recom-binant trimer. Nat. Commun. 9, 3693. https:\/\/doi.org\/10.1038\/s41467-018-06121-4 (2018).","journal-title":"Nat. Commun."},{"issue":"9","key":"14075_CR61","doi-asserted-by":"publisher","first-page":"e1008026","DOI":"10.1371\/journal.ppat.1008026","volume":"15","author":"CC LaBranche","year":"2019","unstructured":"LaBranche, C. C. et al. Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. PLoS Pathog. 15(9), e1008026. https:\/\/doi.org\/10.1371\/journal.ppat.1008026 (2019).","journal-title":"PLoS Pathog."},{"issue":"2","key":"14075_CR62","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1111\/pbi.12981","volume":"17","author":"J Jansing","year":"2019","unstructured":"Jansing, J., Sack, M., Augustine, S. M., Fischer, R. & Bortesi, L. CRISPR\/Cas9-mediated knockout of six glycosyltransferase genes in Nicotiana benthamiana for the production of recombinant proteins lacking \u03b2-1,2-xylose and core \u03b1-1,3-fucose. Plant Biotechnol. J. 17(2), 350\u2013361. https:\/\/doi.org\/10.1111\/pbi.12981 (2019).","journal-title":"Plant Biotechnol. J."},{"issue":"8","key":"14075_CR63","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1016\/j.celrep.2018.07.080","volume":"24","author":"WB Struwe","year":"2018","unstructured":"Struwe, W. B. et al. Site-specific glycosylation of virion-derived HIV-1 Env is mimicked by a soluble trimer immunogen. Cell Rep. 24(8), 1958-1966.e5. https:\/\/doi.org\/10.1016\/j.celrep.2018.07.080 (2018).","journal-title":"Cell Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-14075-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-14075-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-14075-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T05:38:54Z","timestamp":1669354734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-14075-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,15]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["14075"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-14075-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,15]]},"assertion":[{"value":"29 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10027"}}