{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T02:01:47Z","timestamp":1792807307532,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T00:00:00Z","timestamp":1555977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007061","name":"Secretar\u00eda Nacional de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["FID017-2016"],"award-info":[{"award-number":["FID017-2016"]}],"id":[{"id":"10.13039\/501100007061","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerio de Econom\u00eda y Finanzas de Panam\u00e1","award":["009044.060"],"award-info":[{"award-number":["009044.060"]}]},{"name":"Direcci\u00f3n de Investigaci\u00f3n, Universidad Interamericana de Panam\u00e1","award":["DI-UIP633800"],"award-info":[{"award-number":["DI-UIP633800"]}],"id":[{"id":"https:\/\/ror.org\/03grmx823","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Mayaro (MAYV) and Una (UNAV) are emerging arboviruses belonging to the Alphavirus genus of the Togaviridae family. These viruses can produce febrile disease with symptoms such as fever, headache, myalgia, skin rash and incapacitating poly-arthralgia. Serological studies indicate that both viruses are circulating in different countries in Latin America. Viruses need the host cell machinery and resources to replicate effectively. One strategy to find new antivirals consists of identifying key cellular pathways or factors that are essential for virus replication. In this study, we analyzed the role of the ubiquitin-proteasome system (UPS) in MAYV and UNAV replication. Vero-E6 or HeLa cells were treated with the proteasome inhibitors MG132 or Lactacystin, and viral progeny production was quantified using a plaque assay method. In addition, the synthesis of viral proteins was analyzed by Western blot and confocal microscopy. Our results indicate that treatment with proteasome inhibitors decreases MAYV and UNAV protein synthesis, and also causes a significant dose-dependent decrease in MAYV and UNAV replication. Proteasome activity seems to be important at the early stages of MAYV replication. These findings suggest that the ubiquitin-proteasome system is a possible pharmacological target to inhibit these neglected alphaviruses.<\/jats:p>","DOI":"10.3390\/v11040370","type":"journal-article","created":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T03:14:28Z","timestamp":1556075668000},"page":"370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["A Functional Ubiquitin-Proteasome System is Required for Efficient Replication of New World Mayaro and Una Alphaviruses"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3404-1313","authenticated-orcid":false,"given":"Yessica Y.","family":"Llamas-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Grupo de Biolog\u00eda Celular y Molecular de Arbovirus, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panam\u00e1 0816-02593, Panama"},{"name":"Programa de Doctorado en Ciencias Biologicas, Universidad de la Rep\u00fablica, Montevideo 11200, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalkiria","family":"Campos","sequence":"additional","affiliation":[{"name":"Grupo de Biolog\u00eda Celular y Molecular de Arbovirus, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panam\u00e1 0816-02593, Panama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Pascale","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panam\u00e1 0816-02593, Panama"},{"name":"Escuela de Medicina, Universidad de Panam\u00e1, Panam\u00e1, Panama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Arbiza","sequence":"additional","affiliation":[{"name":"Seccci\u00f3n de Virolog\u00eda, Facultad de Ciencias, Universidad de la Rep\u00fablica, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1244-3477","authenticated-orcid":false,"given":"Jos\u00e9","family":"Gonz\u00e1lez-Santamar\u00eda","sequence":"additional","affiliation":[{"name":"Grupo de Biolog\u00eda Celular y Molecular de Arbovirus, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panam\u00e1 0816-02593, Panama"},{"name":"Direcci\u00f3n de Investigaci\u00f3n, Universidad Interamericana de Panam\u00e1, Panam\u00e1 9865, Panama"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.tim.2013.03.003","article-title":"Urbanization and geographic expansion of zoonotic arboviral diseases: Mechanisms and potential strategies for prevention","volume":"21","author":"Weaver","year":"2013","journal-title":"Trends Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1089\/vbz.2016.1952","article-title":"Emergence of Human Arboviral Diseases in the Americas, 2000\u20132016","volume":"16","author":"Vasconcelos","year":"2016","journal-title":"Vector-Borne Zoonotic Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.antiviral.2009.10.008","article-title":"Present and future arboviral threats","volume":"85","author":"Weaver","year":"2010","journal-title":"Antiviral Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1093\/jme\/tjw209","article-title":"Emergent and reemergent arboviruses in South America and the Caribbean: Why so many and why now?","volume":"54","author":"Marcondes","year":"2017","journal-title":"J. Med. Entomol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1590\/0037-8682-0246-2014","article-title":"Emerging alphaviruses in the americas: Chikungunya and mayaro","volume":"47","author":"Figueiredo","year":"2014","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_6","first-page":"163","article-title":"Mayaro: an emerging viral threat?","volume":"7","author":"Monsalve","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.4269\/ajtmh.1957.6.1012","article-title":"Mayaro virus: a new human disease agent. II. Isolation from blood of patients in Trinidad, B.W.I","volume":"6","author":"Anderson","year":"1957","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"750","DOI":"10.4269\/ajtmh.2011.11-0359","article-title":"Experimental transmission of Mayaro virus by Aedes aegypti","volume":"85","author":"Long","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/mve.12322","article-title":"Transmission potential of Mayaro virus in Florida Aedes aegypti and Aedes albopictus mosquitoes","volume":"32","author":"Wiggins","year":"2018","journal-title":"Med. Vet. Entomol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1086\/515070","article-title":"Mayaro Virus Disease: An Emerging Mosquito-Borne Zoonosis in Tropical South America","volume":"28","author":"Tesh","year":"1999","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Santiago, F.W., Halsey, E.S., Siles, C., Vilcarromero, S., Guevara, C., Silvas, J.A., Ramal, C., Ampuero, J.S., and Aguilar, P.V. (2015). Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0004104"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"682","DOI":"10.4269\/ajtmh.1981.30.682","article-title":"An outbreak of Mayaro virus disease in Belterra, Brazil. II. Epidemiology","volume":"30","author":"LeDuc","year":"1981","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1089\/vbz.2011.0669","article-title":"Mayaro Fever in the City of Manaus, Brazil, 2007\u20132008","volume":"12","author":"Gimaque","year":"2012","journal-title":"Vector-Borne Zoonotic Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.3201\/eid1911.130777","article-title":"Mayaro virus infection, Amazon Basin region, Peru, 2010\u20132013","volume":"19","author":"Halsey","year":"2013","journal-title":"Emerg. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.3201\/eid0910.030161","article-title":"Mayaro virus in wild mammals, French Guiana","volume":"9","author":"Gardon","year":"2003","journal-title":"Emerg. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.3201\/eid1007.030860","article-title":"Family cluster of Mayaro fever, Venezuela","volume":"10","author":"Torres","year":"2004","journal-title":"Emerg. Infect. Dis."},{"key":"ref_17","first-page":"288","article-title":"Virus Mayaro: un arbovirus reemergente en Venezuela y Latinoam\u00e9rica","volume":"32","author":"Navarro","year":"2012","journal-title":"Biom\u00e9dica"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"317","DOI":"10.4103\/0974-777X.91049","article-title":"Hunting in the rainforest and mayaro virus infection: An emerging alphavirus in Ecuador","volume":"3","author":"Izurieta","year":"2011","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.4269\/ajtmh.1966.15.385","article-title":"An ecological survey for arboviruses in Almirante, Panama, 1959\u20131962","volume":"15","author":"Galindo","year":"1966","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.4269\/ajtmh.17-0679","article-title":"Human and equine infection with alphaviruses and flaviviruses in panam\u00e1 during 2010: A cross-Sectional study of household contacts during an encephalitis outbreak","volume":"98","author":"Carrera","year":"2018","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.3201\/eid2211.161015","article-title":"Mayaro virus in child with acute febrile illness, Haiti, 2015","volume":"22","author":"Lednicky","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hotez, P.J., and Murray, K.O. (2017). Dengue, West Nile virus, chikungunya, Zika-and now Mayaro?. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005462"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.virusres.2005.11.006","article-title":"Mayaro virus: Complete nucleotide sequence and phylogenetic relationships with other alphaviruses","volume":"117","author":"Lavergne","year":"2006","journal-title":"Virus Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"461","DOI":"10.4269\/ajtmh.2006.75.461","article-title":"Genetic relationships among Mayaro and Una viruses suggest distinct patterns of transmission","volume":"75","author":"Powers","year":"2006","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"777","DOI":"10.4269\/ajtmh.1963.12.777","article-title":"Aura and Una, Two New Group A Arthropod-Borne Viruses","volume":"12","author":"Causey","year":"1963","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.4269\/ajtmh.1966.15.369","article-title":"Isolation and characterization of arboviruses from Almirante, Republic of Panama","volume":"15","author":"Peralta","year":"1966","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_27","first-page":"409","article-title":"Arboviruses isolated from mosquitos and man in Surinam","volume":"27","author":"Haas","year":"1975","journal-title":"Trop. Geogr. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"483","DOI":"10.4269\/ajtmh.1984.33.483","article-title":"Arbovirus studies in southwestern Venezuela during 1973\u20131981. II. Isolations and further studies of Venezuelan and eastern equine encephalitis, Una, Itaqui, and Moju viruses","volume":"33","author":"Walder","year":"1984","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.trstmh.2007.04.009","article-title":"Infection by UNA virus (Alphavirus; Togaviridae) and risk factor analysis in black howler monkeys (Alouatta caraya) from Paraguay and Argentina","volume":"101","author":"Contigiani","year":"2007","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1590\/S0036-46652003000200012","article-title":"Una virus: First report of human infection in Argentina","volume":"45","author":"Diaz","year":"2003","journal-title":"Rev. Inst. Med. Trop. Sao Paulo"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1089\/vbz.2017.2178","article-title":"Alphaviruses: Serological Evidence of Human Infection in Paraguay (2012\u20132013)","volume":"18","author":"Cardozo","year":"2018","journal-title":"Vector-Borne Zoonotic Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.chom.2009.05.012","article-title":"Ubiquitination, Ubiquitin-like Modifiers, and Deubiquitination in Viral Infection","volume":"5","author":"Isaacson","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.lfs.2018.06.014","article-title":"Pleiotropic roles of the ubiquitin-proteasome system during viral propagation","volume":"207","author":"Tang","year":"2018","journal-title":"Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.cell.2010.11.012","article-title":"Ubiquitin: Same molecule, different degradation pathways","volume":"143","author":"Clague","year":"2010","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/cr.2016.39","article-title":"Ubiquitin modifications","volume":"26","author":"Swatek","year":"2016","journal-title":"Cell Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.mib.2010.05.012","article-title":"Viral hijacking of the host ubiquitin system to evade interferon responses","volume":"13","author":"Viswanathan","year":"2010","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1128\/JVI.01631-10","article-title":"Rotavirus Replication Requires a Functional Proteasome for Effective Assembly of Viroplasms","volume":"85","author":"Contin","year":"2011","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.1128\/JVI.07039-11","article-title":"Hepatitis E Virus Replication Requires an Active Ubiquitin-Proteasome System","volume":"86","author":"Karpe","year":"2012","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Barrado-Gil, L., Galindo, I., Mart\u00ednez-Alonso, D., Viedma, S., and Alonso, C. (2017). The ubiquitin-proteasome system is required for African swine fever replication. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189741"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.virol.2014.03.028","article-title":"The ubiquitin-proteasome system is required for the early stages of porcine circovirus type 2 replication","volume":"456\u2013457","author":"Cheng","year":"2014","journal-title":"Virology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9625","DOI":"10.1128\/JVI.01048-10","article-title":"Inhibition of the Ubiquitin-Proteasome System Affects Influenza A Virus Infection at a Postfusion Step","volume":"84","author":"Widjaja","year":"2010","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.virusres.2009.12.010","article-title":"Decreased replication of human respiratory syncytial virus treated with the proteasome inhibitor MG-132","volume":"149","author":"Lupfer","year":"2010","journal-title":"Virus Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7180","DOI":"10.1128\/JVI.00541-12","article-title":"Evasion of the Innate Immune Response: the Old World Alphavirus nsP2 Protein Induces Rapid Degradation of Rpb1, a Catalytic Subunit of RNA Polymerase II","volume":"86","author":"Akhrymuk","year":"2012","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Amaya, M., Keck, F., Lindquist, M., Voss, K., Scavone, L., Kehn-Hall, K., Roberts, B., Bailey, C., Schmaljohn, C., and Narayanan, A. (2015). The ubiquitin proteasome system plays a role in Venezuelan equine encephalitis virus infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124792"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0962-8924(98)01346-4","article-title":"Proteasome inhibitors: Valuable new tools for cell biologists","volume":"8","author":"Lee","year":"1998","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8545","DOI":"10.1074\/jbc.273.15.8545","article-title":"Lactacystin, proteasome function, and cell fate","volume":"273","author":"Fenteany","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12890","DOI":"10.1128\/JVI.05628-11","article-title":"Regulation of vaccinia virus E3 protein by small ubiquitin-like modifier proteins","volume":"85","author":"Campagna","year":"2011","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1093\/emboj\/19.1.94","article-title":"Recognition of the polyubiquitin proteolytic signal","volume":"19","author":"Thrower","year":"2000","journal-title":"EMBO J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1007\/s11262-016-1355-5","article-title":"Activities of proteasome and m-calpain are essential for Chikungunya virus replication","volume":"52","author":"Karpe","year":"2016","journal-title":"Virus Genes"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1177\/135965350601100805","article-title":"Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: Role of nuclear factor-\u03baB","volume":"11","author":"Amici","year":"2006","journal-title":"Antivir. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/j.1348-0421.2005.tb03672.x","article-title":"Cell-specific inhibition of paramyxovirus maturation by proteasome inhibitors","volume":"49","author":"Watanabe","year":"2005","journal-title":"Microbiol. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10623","DOI":"10.1128\/JVI.75.22.10623-10629.2001","article-title":"Rhabdoviruses and the Cellular Ubiquitin-Proteasome System: a Budding Interaction","volume":"75","author":"Harty","year":"2001","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13057","DOI":"10.1073\/pnas.97.24.13057","article-title":"Proteasome inhibition interferes with Gag polyprotein processing, release, and maturation of HIV-1 and HIV-2","volume":"97","author":"Schubert","year":"2000","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1128\/JVI.01986-08","article-title":"Inhibition of the Ubiquitin-Proteasome System Prevents Vaccinia Virus DNA Replication and Expression of Intermediate and Late Genes","volume":"83","author":"Satheshkumar","year":"2009","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/156800911794519752","article-title":"Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives","volume":"11","author":"Chen","year":"2011","journal-title":"Curr. 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