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dc.contributor.creatorStack, Julianne
dc.contributor.creatorHurst, Tara P.
dc.contributor.creatorFlannery, Sinead M.
dc.contributor.creatorBrennan, Kiva
dc.contributor.creatorRupp, Sebastian
dc.contributor.creatorOda, Shun-ichiro
dc.contributor.creatorKhan, Amir R.
dc.contributor.creatorBowie, Andrew G.
dc.date.accessioned2019-02-26T14:33:57Z
dc.date.available2019-02-26T14:33:57Z
dc.date.issued2013
dc.identifier.citationStack, J. et al. Poxviral protein A52 stimulates p38 Mitogen-Activated Protein Kinase (MAPK) activation by causing tumor necrosis factor receptor-associated factor 6 (TRAF6) self-association leading to transforming growth factor b-activated kinase 1 (TAK1) recruitment. J. Biol. Chem. 2013, 288(47):33642-53.en_US
dc.identifier.urihttp://hdl.handle.net/10395/2681
dc.descriptionPoxviral protein A52 stimulates p38 Mitogen-Activated Protein Kinase (MAPK) activation by causing tumor necrosis factor receptor-associated factor 6 (TRAF6) self-association leading to transforming growth factor b-activated kinase 1 (TAK1) recruitment.en_US
dc.description.abstractVaccinia virus encodes a number of proteins that inhibit and manipulate innate immune signaling pathways that also have a role in virulence. These include A52, a protein shown to inhibit IL-1- and Toll-like receptor-stimulated NF B activation, via interaction with interleukin-1 receptor-associated kinase 2 (IRAK2). Interestingly, A52 was also found to activate p38 MAPK and thus enhance Toll-like receptor-dependent IL-10 induction, which was TRAF6-dependent, but the manner in which A52 manipulates TRAF6 to stimulate p38 activation was unclear. Here, we show that A52 has a non-canonical TRAF6- binding motif that is essential for TRAF6 binding and p38 activation but dispensable for NF B inhibition and IRAK2 interaction. Wild-type A52, but not a mutant defective in p38 activation and TRAF6 binding (F154A), caused TRAF6 oligomerization and subsequent TRAF6-TAK1 association. The crystal structure of A52 shows that it adopts a Bcl2-like fold and exists as a dimer in solution. Residue Met-65 was identified as being located in the A52 dimer interface, and consistent with that, A52-M65E was impaired in its ability to dimerize. A52-M65E although capable of interacting with TRAF6, was unable to cause either TRAF6 self-association, induce the TRAF6-TAK1 association, or activate p38 MAPK. The results suggest that an A52 dimer causes TRAF6 self-association, leading to TAK1 recruitment and p38 activation. This reveals a molecular mechanism whereby poxviruses manipulate TRAF6 to activate MAPKs (which can be proviral) without stimulating antiviral NF B activation.en_US
dc.language.isoengen_US
dc.publisherASBMB [American Society for Biochemistry and Molecular Biology]en_US
dc.relation.ispartofseries288;47
dc.rights.urihttp://www.jbc.org/content/288/47/33642.longen_US
dc.subjectPoxviral proteinen_US
dc.subjectA52en_US
dc.subjectp38en_US
dc.subjectMitogen-Activated Protein Kinase (MAPK)en_US
dc.subjectTumor necrosis factor receptor-associated factor 6 (TRAF6)en_US
dc.subjectTransforming growth factor b-activated kinase 1 (TAK1)en_US
dc.subjectRecruitmenten_US
dc.subjectGrowthen_US
dc.titlePoxviral protein A52 stimulates p38 Mitogen-Activated Protein Kinase (MAPK) activation by causing tumor necrosis factor receptor-associated factor 6 (TRAF6) self-association leading to transforming growth factor b-activated kinase 1 (TAK1) recruitmenten_US
dc.typeArticleen_US
dc.type.supercollectionall_mic_researchen_US
dc.type.supercollectionmic_published_revieweden_US
dc.description.versionYesen_US
dc.identifier.doi10.1074/jbc.M113.485490


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