Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recruitment of components of the ubiquitin proteasome system. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Here we present evidence that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. We show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, we show that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.

Background: Cholesterol transporters ABCA1 and ABCG1 export excess cellular cholesterol and protect against atherosclerosis. Results: Cholesterol loading decreases cellular degradation of ABCA1 and ABCG1 and also their ubiquitination. Conclusion: Cholesterol-dependent suppression of ABCA1 and ABCG1 ubiquitination decreases their proteasomal degradation. Significance: This mechanism enhances the capacity of cholesterol-loaded cells to export their excess cholesterol.

Background: Cholesterol-loaded macrophages are key mediators of atherosclerosis and demonstrate increased SMPDL3A expression and secretion. Results: SMPDL3A expression is stimulated by cholesterol, liver X receptor ligands, and cAMP and hydrolyzes nucleotide phosphates. Conclusion: SMPDL3A is a nucleotide phosphodiesterase secreted from cholesterol-loaded macrophages. Significance: SMPDL3A possesses a novel enzymatic activity with potential relevance to atherosclerosis.

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from cells to HDL, which is the fi rst step of the reverse cholesterol transport pathway ( 1, 2 ). Although no human phenotype has been described as being associated with ABCG1 ablation, studies in animals and cell culture models suggest that its main role lies in the protection of macrophages and other vascular cells from cholesterol accumulation, a process that is thought to be an important step in the development of atherosclerosis ( 3, 4 ).We have previously shown that ABCG1 can potentially synergise with ABCA1, another ABC transporter, whereby ABCA1 donates cholesterol and phospholipids to lipidfree apolipoprotein A-I, which in turn can be further lipidated by ABCG1 ( 5 ). This cooperative function of the two transporters may be important in the developing atherosclerotic plaque, where there might be restricted access to larger HDL particles. Understanding how these ABC transporters function in macrophages and how they can be stimulated will provide opportunities to increase reverse cholesterol transport in the vessel wall. The transcriptional regulation of ABCG1 as a well-established target gene of the liver X receptor (LXR) is reasonably well understood, with cholesterol accumulation increasing and cholesterol removal reducing gene expression ( 6 ). However, the posttranslational control of the transporter is relatively unexplored at present.One aspect that makes ABCG1 a complex and intriguing transporter is the fact that more than one protein isoform is expressed in human cells. Several N-terminal variants have been proposed based on different translational start sites, but these have not been characterized to Abstract ABCG1 is an ABC half-transporter that exports cholesterol from cells to HDL. This study set out to investigate differences in posttranslational processing of two human ABCG1 protein isoforms, termed ABCG1(+12) and ABCG1 (