title: Recruitment of the oncoprotein v-ErbA to aggresomes.
abstract: Aggresome formation, a cellular response to misfolded protein aggregates, is linked to cancer and neurodegenerative disorders. Previously we showed that Gag-v-ErbA (v-ErbA), a retroviral variant of the thyroid hormone receptor (TRα1), accumulates in and sequesters TRα1 into cytoplasmic foci. Here, we show that foci represent v-ErbA targeting to aggresomes. v-ErbA colocalizes with aggresomal markers, proteasomes, hsp70, HDAC6, and mitochondria. Foci have hallmark characteristics of aggresomes: formation is microtubule-dependent, accelerated by proteasome inhibitors, and they disrupt intermediate filaments. Proteasome-mediated degradation is critical for clearance of v-ErbA and T(3)-dependent TRα1 clearance. Our studies highlight v-ErbA's complex mode of action: the oncoprotein is highly mobile and trafficks between the nucleus, cytoplasm, and aggresome, carrying out distinct activities within each compartment. Dynamic trafficking to aggresomes contributes to the dominant negative activity of v-ErbA and may be enhanced by the viral Gag sequence. These studies provide insight into novel modes of oncogenesis across multiple cellular compartments.
authors.affiliation: Department of Biological Sciences, Hampton University, Hampton, VA 23668, United States.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Bondzi
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Brunner
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Munyikwa
authors.forename: Crystal D
authors.initials: CD
authors.lastname: Connor
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Simmons
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stephens
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Belt
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Roggero
authors.forename: Manohara S
authors.initials: MS
authors.lastname: Mavinakere
authors.forename: Shantá D
authors.initials: SD
authors.lastname: Hinton
authors.forename: Lizabeth A
authors.initials: LA
authors.lastname: Allison
mesh_terms: D001355:Alpharetrovirus / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D007382:Intermediate Filaments / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018774:Oncogene Proteins v-erbA / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015683:Gene Products, gag; D018840:HSP70 Heat-Shock Proteins; D018774:Oncogene Proteins v-erbA; D011993:Recombinant Fusion Proteins; D014746:Vimentin; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D004398:Dyneins