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 T3-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.

Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor

“…Our prior studies have shown that in HeLa cells overexpression of wild-type TR does not saturate the capacity of the nuclear import machinery, nor do fluorescent protein tags alter localization patterns. Further, wild-type TR is primarily nuclear over a wide range of expression levels in transfected cells, 31,[35][36][37]65 and supports T 3 -dependent gene transactivation in reporter assays. 69 Finally, distribution patterns of exogenous TRs in HeLa cells are the same as in cell lines that express endogenous TRs, including HepG2 (hepatocellular carcinoma) cells that express low levels of TRα1 and TRβ1, and GH4C1 (rat pituitary tumor) cells that express high levels of both TRα1 and TRβ1.…”

“…Along with a NLS in the hinge domain (NLS‐1), TRα1 houses a NLS in the A/B domain that is absent in TRβ1 and inactive in the retroviral oncoprotein v‐ErbA . v‐ErbA is a dominant negative mutant of TRα1 that displays altered transport activity due to acquisition of a viral CRM1 (exportin 1)‐dependent NES and localizes to both the nucleus and cytosol at steady‐state . TRα1 exits the nucleus through two pathways, one dependent on the export factors CRM1 and calreticulin, and the other CRM1‐independent, mediated by NESs in helix H3 (NES‐H3), helix H6 (NES‐H6), and helix 12 (NES‐H12) of the ligand‐binding domain (LBD) of TR .…”

“…32 v-ErbA is a dominant negative mutant of TRα1 that displays altered transport activity due to acquisition of a viral CRM1 (exportin 1)-dependent NES and localizes to both the nucleus and cytosol at steady-state. [35][36][37][38] TRα1 exits the nucleus through two pathways, one dependent on the export factors CRM1 and calreticulin, and the other CRM1independent, 39 mediated by NESs in helix H3 (NES-H3), helix H6 (NES-H6), and helix 12 (NES-H12) of the ligandbinding domain (LBD) of TR. 32 Given that TR contains multiple, conflicting nuclear import and export signals, it is of interest to ascertain what factors modulate TR nuclear retention.…”

Characterization of aggregate/aggresome structures formed by polyhedrin of Bombyx mori nucleopolyhedrovirus

“…Next, whether polyhedrin foci possess other hallmark characteristics of aggresomes was demonstrated. Formation of aggresomes has been reported to recruit cytosolic components such as chaperones, ubiquitinated proteins and mitochondria, to facilitate clearance of aggregated proteins 27 28 . To characterize further that polyhedrin aggregates are aggresomes, association of HSC/HSP70, ubiquitin and mitochondria with polyhedrin was investigated.…”

Cellular defence or viral assist: the dilemma of HDAC6

“…Interestingly, increasing evidence suggests that the replication or assembly of many viruses, such as poxviruses, African swine fever virus, iridoviruses and phycodnaviruses, occurs in large insoluble inclusion bodies called 'viral factories', which are generally localized near the MTOC and share several features with pericentriolar aggresomes [118]. Besides, several viruses induce aggresomes and autophagosomes to generate sites of replication or assembly [119,120], and viral oncoproteins are recruited to aggresomes by interacting with HDAC6 [121,122]. Whether the aggresome pathway represents an adaptive niche for virus infection and detailed mechanism needs to be further defined.…”