{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:26:23Z","timestamp":1785803183674,"version":"3.56.0"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"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":["R01 AI114467;  R01 AI108546 ; R21 AI135917"],"award-info":[{"award-number":["R01 AI114467;  R01 AI108546 ; R21 AI135917"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, the E3 proteins unique to HAdVs-F have not been characterized and the mechanism by which HAdVs-F evade immune defenses in the gastrointestinal (GI) tract is poorly understood. Here, we show that HAdV-F41 infection of human intestinal HCT116 cells upregulated the expression of MHC class I-related chain A (MIC A) and MIC B relative to uninfected cells. Our results also showed that, for MIC B, this response did not however result in a significant increase of MIC B on the cell surface. Instead, MIC B was largely sequestered intracellularly. Thus, although HAdV-F41 infection of HCT116 cells upregulated MIC B expression, the ligand remained inside infected cells. A similar observation could not be made for MIC A in these cells. Our preliminary findings represent a novel function of HAdVs-F that may enable these viruses to evade immune surveillance by natural killer (NK) cells in the infected gut, thereby paving the way for the future investigation of their unique E3 proteins.<\/jats:p>","DOI":"10.3390\/v13071289","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T21:55:52Z","timestamp":1625176552000},"page":"1289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8606-7454","authenticated-orcid":false,"given":"Edson R. A.","family":"Oliveira","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Bouvier","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"ref_1","unstructured":"Fields, B.N., Knipe, D.M., and Howley, P.M. (2013). Adenoviridae. Fields Virology, Wolters Kluwer Health\/Lippincott Williams & Wilkins. [6th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1128\/CMR.00116-13","article-title":"Adenovirus infections in immunocompromised patients","volume":"27","author":"Lion","year":"2014","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1097\/MOT.0b013e3283324e1b","article-title":"Adenovirus infections in solid organ transplant recipients","volume":"14","author":"Hoffman","year":"2009","journal-title":"Curr. Opin. Organ. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.cmi.2015.03.011","article-title":"Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: Clues for antiviral preemptive treatment","volume":"21","author":"Feghoul","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/jpids\/piy049","article-title":"Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric hematopoietic cell transplant patients","volume":"8","author":"Fisher","year":"2018","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1023\/A:1008135928310","article-title":"Immunomodulatory functions encoded by the E3 transcription unit of adenoviruses","volume":"21","author":"Burgert","year":"2000","journal-title":"Virus Genes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0042-6822(91)90815-S","article-title":"Region E3 of adenovirus: A cassette of genes involved in host immunosurveillance and virus-cell interactions","volume":"184","author":"Wold","year":"1991","journal-title":"Virology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1002\/j.1460-2075.1987.tb02466.x","article-title":"The E3\/19K protein of adenovirus type 2 binds to the domains of histocompatibility antigens required for CTL recognition","volume":"6","author":"Burgert","year":"1987","journal-title":"EMBO J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/S0092-8674(85)80079-9","article-title":"An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens","volume":"41","author":"Burgert","year":"1985","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5674","DOI":"10.1073\/pnas.75.11.5674","article-title":"Molecular association between transplantation antigens and cell surface antigen in adenovirus-transformed cell line","volume":"75","author":"Kvist","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0092-8674(87)90226-1","article-title":"A short sequence in the COOH terminus makes an adenovirus membrane glycoprotein a resident of the endoplasmic reticulum","volume":"50","author":"Paabo","year":"1987","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6104","DOI":"10.1128\/JVI.03391-12","article-title":"The transmembrane domain of the adenovirus E3\/19K protein acts as an endoplasmic reticulum retention signal and contribute to intracellular sequestration of major histocompatibility complex class I molecules","volume":"87","author":"Sester","year":"2013","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1084\/jem.174.6.1629","article-title":"Retention of adenovirus E19 glycoprotein in the endoplasmic reticulum is essential to its ability to block antigen presentation","volume":"174","author":"Cox","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13317","DOI":"10.1128\/JVI.79.21.13317-13325.2005","article-title":"The endoplasmic reticulum lumenal domain of the adenovirus type 2 E3-19K binds to peptide-filled and peptide-deficient HLA-A*1101 molecules","volume":"79","author":"Liu","year":"2005","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4567","DOI":"10.4049\/jimmunol.178.7.4567","article-title":"Allele- and locus-specific recognition of class I MHC molecules by the immunomodulatory E3-19K protein from adenovirus","volume":"178","author":"Liu","year":"2007","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17631","DOI":"10.1074\/jbc.M110.212050","article-title":"Adenovirus E3-19K proteins of different serotypes and subgroups have similar, yet distinct, immunomodulatory functions towards major histocompatibility class I molecules","volume":"286","author":"Fu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.molimm.2010.10.017","article-title":"Determinants of the endoplasmic reticulum (ER) lumenal-domain of the Adenovirus serotype 2 E3-19K protein for association with and ER-retention of major histocompatibility complex class I molecules","volume":"48","author":"Fu","year":"2011","journal-title":"Mol. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6314","DOI":"10.1128\/jvi.70.9.6314-6322.1996","article-title":"Human adenovirus-specific CD8+ T-cell responses are not inhibited by E3-19K in the presence of gamma interferon","volume":"70","author":"Flomenberg","year":"1996","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3960","DOI":"10.4049\/jimmunol.138.11.3960","article-title":"Reduced allorecognition of adenovirus-2 infected cells","volume":"138","author":"Andersson","year":"1987","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1073\/pnas.84.5.1356","article-title":"\u201cE3\/19K\u201d protein of adenovirus type 2 inhibits lysis of cytolytic T lymphocytes by blocking cell surface expression of histocompatibility class I antigens","volume":"84","author":"Burgert","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0042-6822(88)90580-6","article-title":"Differential effect of adenovirus 2 E3\/19K glycoprotein on the expression of H-2Kb and H-2Db class I antigens and H-2Kb- and H-2Db-restricted SV40-specific CTL-mediated lysis","volume":"165","author":"Tanaka","year":"1988","journal-title":"Virology"},{"key":"ref_22","first-page":"3960","article-title":"Mouse anti-adenovirus cytoxic T lymphocytes","volume":"138","author":"Rawle","year":"1989","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/nsmb.2396","article-title":"Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation","volume":"19","author":"Li","year":"2012","journal-title":"Nat. Struc. Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.4049\/jimmunol.1600541","article-title":"Structure of the Adenovirus Type 4 (Species E) E3-19K\/HLA-A2 complex reveals species-specific features in MHC I recognition","volume":"197","author":"Li","year":"2016","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1002\/1873-3468.13682","article-title":"Immune evasion by adenoviruses: A window into host-virus adaptation","volume":"593","author":"Oliveira","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/j.1348-0421.2012.00469.x","article-title":"Detection and molecular characterization of adenoviruses in Korean children hospitalized with acute gastroenteretitis","volume":"56","author":"Lee","year":"2012","journal-title":"Microbiol. Immunol."},{"key":"ref_27","first-page":"142912","article-title":"Genetic diversity of human adenov\u00edrus in children with acute gastreoenteretitis, Albania, 2013\u20132015","volume":"2015","author":"LaRosa","year":"2015","journal-title":"Biomed. Res. Intern."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Afrad, M.H., Avzun, T., Haque, J., Haguw, W., Hossain, M.E., Rahman, A.F.M.R., Ahmed, S., Faruque, A.S.G., Rahman, M.Z., and Rahman, M. (2017). Detection of enteric- and non-enteric adenoviruses in gastreoenteretitis patients, Bangladesh, 2012\u20132015. J. Med. Virol.","DOI":"10.1002\/jmv.25008"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kumthip, K., Khamrin, P., Ushijima, H., and Maneekarn, N. (2019). Enteric- and non-enteric adenoviruses associated with acute gastreoenteretitis in pediatric patients in Thailand, 2011 to 2017. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220263"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1006\/jmbi.1993.1687","article-title":"The DNA sequence of adenovirus type 40","volume":"234","author":"Davison","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1006\/viro.1994.1664","article-title":"Phylogenetic relationships among adenovirus serotypes","volume":"205","author":"Bailey","year":"1994","journal-title":"Virology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1128\/jvi.70.4.2658-2663.1996","article-title":"Genetic organization, size, and complete sequence of early region 3 genes of human adenovirus type 41","volume":"70","author":"Yeh","year":"1996","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kosulin, K. (2019). Intestinal HAdV infection: Tissue specificity, persistence, and implications for antiviral therapy. Viruses, 11.","DOI":"10.3390\/v11090804"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1128\/jcm.17.2.360-364.1983","article-title":"Adenovirus hexon monoclonal antibody that is group specific and potentially useful as a diagnostic reagent","volume":"17","author":"Cepko","year":"1983","journal-title":"J. Clin. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41587-019-0036-z","article-title":"SignalP 5.0 improves signal peptide predictions using deep neural networks","volume":"37","author":"Armenteros","year":"2019","journal-title":"Nat. Biotech."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"D458","DOI":"10.1093\/nar\/gkaa937","article-title":"SMART: Recent updates, new developments and status in 2020","volume":"49","author":"Letunic","year":"2020","journal-title":"Nucleic Acid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1006\/jmbi.2000.4315","article-title":"Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes","volume":"305","author":"Krogh","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_38","unstructured":"Kelley, L., and Jefferys, B. (2011). Phyre2: Protein Homology\/Analogy Recognition Engine V 2.0, Structural Bioinformatics Group, Imperial College."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Moncaya, G., Lin, D., McCarthy, M.T., Watson, A.A., and O\u2019Calaghan, C.A. (2017). MICA expression is regulated by cell adhesion and contact in a FAK\/Src-dependent manner. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00687"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5978","DOI":"10.1128\/JVI.02650-06","article-title":"New adenoviruses species found in a patient presenting with gastroenteritis","volume":"81","author":"Jones","year":"2007","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1099\/vir.0.19497-0","article-title":"Genetic content and evolution of adenoviruses","volume":"84","author":"Davison","year":"2003","journal-title":"J. Gen. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.1128\/jvi.70.5.2832-2841.1996","article-title":"Early region 3 adenovirus type 19 (subgroup D) encodes an HLA-binding protein distinct from that of subgroups B and C","volume":"70","author":"Deryckere","year":"1996","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1006\/viro.1994.1266","article-title":"The signal-anchor domain of adenovirus E3-6.7K, a type III integral membrane protein can direct adenovirus E3-gp19K, a type I integral membrane protein, into the membrane of the endoplasmic reticulum","volume":"201","author":"Deutscher","year":"1994","journal-title":"Virology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.1074\/jbc.M008218200","article-title":"Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2","volume":"276","author":"Benedict","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1128\/jvi.68.2.1239-1244.1994","article-title":"Adenoviruses type 40 and 41 growth in vitro: Host range diversity reflected by differences in patterns of DNA replication","volume":"68","author":"Tiemessen","year":"1994","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/jmv.1890110305","article-title":"Candidate adenoviruses 40 and 41: Fastidious adenoviruses from human infant stool","volume":"11","year":"1983","journal-title":"J. Med. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/0166-0934(88)90133-4","article-title":"Comparison of enteric adenovirus infection in various human cell lines","volume":"20","author":"Witt","year":"1988","journal-title":"J. Virol. Methods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1006\/viro.1993.1009","article-title":"Adenovirus type 40 virions contain two distinct fibers","volume":"192","author":"Kidd","year":"1983","journal-title":"Virology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0168-1702(94)90054-X","article-title":"Human adenovirus type 41 contains two fibers","volume":"33","author":"Yeh","year":"1994","journal-title":"Virus Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0168-1702(99)00087-8","article-title":"Adenovirus type 41 lacks an RGD alpha(v)-integrin binding motif on the penton base and undergoes delayed uptake in A549 cells","volume":"64","author":"Albinsson","year":"1999","journal-title":"Virus Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.coi.2007.11.002","article-title":"Immune evasion of natural killer cells by viruses","volume":"20","author":"Jonjic","year":"2008","journal-title":"Curr. Opin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S1074-7613(01)00095-4","article-title":"ULPBs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulates NK cytotoxicity through NKG2D receptor","volume":"14","author":"Cosman","year":"2001","journal-title":"Immunity"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"12345","DOI":"10.1128\/JVI.01175-09","article-title":"NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142","volume":"83","author":"Ashiru","year":"2009","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Schneider, C.L., and Hudson, A.W. (2011). The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytotoxicity through modulation of MICA and MICB. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002362"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1073\/pnas.0707883105","article-title":"Down-regulation of NKG2D and NKp80 ligands by Kaposi\u2019s sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity","volume":"105","author":"Thomas","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4585","DOI":"10.1128\/JVI.02251-07","article-title":"Adenovirus E3\/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B","volume":"82","author":"McSharry","year":"2008","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"255","DOI":"10.4049\/jimmunol.0902343","article-title":"Conserved amino acids within the adenovirus 2 E3\/19K protein differentially affect downregulation of MHC class I and MICA\/B proteins","volume":"184","author":"Sester","year":"2010","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.imlet.2012.03.001","article-title":"Tumorigenic adenovirus 12 cells evade NK cell lysis by reducing the expression of NKG2D ligands","volume":"4","author":"Heyward","year":"2012","journal-title":"Immunol. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Smith, J.G., Silvestry, M., Lindert, S., Lu, W., Nemerow, G.R., and Stewart, P.L. (2010). Insights into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000959"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e00250-18","DOI":"10.1128\/JVI.00250-18","article-title":"Adenovirus infections of human enteroids reveals interferon sensitivity and preferential infection of globlet cells","volume":"92","author":"Holly","year":"2018","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:55Z","timestamp":1760163895000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,1]]},"references-count":60,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["v13071289"],"URL":"https:\/\/doi.org\/10.3390\/v13071289","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,1]]}}}