Abstract
ABSTRACTIn conditions of proteasomal impairment, the build-up of damaged or misfolded proteins activates a cellular response leading to the recruitment of damaged proteins into perinuclear aggregates called aggresomes. Aggresome formation involves the retrograde transport of cargo proteins along the microtubule network and is dependent on the histone deacetylase HDAC6. Here we show that ionizing radiation (IR) promotes Ran-Binding Protein M (RanBPM) relocalization into discrete perinuclear foci where it co-localizes with aggresome components ubiquitin, dynein and HDAC6, suggesting that the RanBPM perinuclear clusters correspond to aggresomes. RanBPM was also recruited to aggresomes following treatment with the proteasome inhibitor MG132 and the DNA-damaging agent etoposide. Strikingly, aggresome formation by HDAC6 was markedly impaired in RanBPM shRNA cells, but was restored by re-expression of RanBPM. RanBPM was found to interact with HDAC6 and to inhibit its deacetylase activity. This interaction was abrogated by a RanBPM deletion of its LisH/CTLH domain, which also prevented aggresome formation, suggesting that RanBPM promotes aggresome formation through an association with HDAC6. Our results suggest that RanBPM regulates HDAC6 activity and is a central regulator of aggresome formation.
Highlights
Misfolded proteins are generally processed by chaperonemediated refolding or by proteasomal degradation through the ubiquitin–proteasome system (UPS) (Schwartz and Ciechanover, 2009; Wojcik and DeMartino, 2003)
Ran-Binding Protein M (RanBPM) is recruited to aggresomes in response to ionizing radiation (IR) and proteasome inhibition We previously reported that IR treatment induces RanBPM relocalization from the nucleus to the cytoplasm (Atabakhsh et al, 2009)
We present evidence that RanBPM forms a complex with HDAC6 and inhibits HDAC6 activity and that RanBPM function in aggresome formation is dependent on its association with HDAC6
Summary
Misfolded proteins are generally processed by chaperonemediated refolding or by proteasomal degradation through the ubiquitin–proteasome system (UPS) (Schwartz and Ciechanover, 2009; Wojcik and DeMartino, 2003). In addition to aggregated proteins, aggresomes recruit several other components, including chaperones, for instance heat shock protein 70 (Hsp70), ubiquitin and ubiquitination enzymes such as ataxin 3 (AT3) and carboxy terminus of Hsp70-interacting protein (CHIP), as well as proteasome components and motor proteins such as dynein and dynamitin (Garcia-Mata et al, 2002; Johnston et al, 2002; Chin et al, 2008; Rodriguez-Gonzalez et al, 2008; Yao, 2010; Zhang and Qian, 2011). The histone deacetylase HDAC6 has been shown to be an essential component of the aggresome pathway, by functioning as a key factor recruiting protein cargo to the dynein motor for transport into the aggresome and by regulating a cell response pathway involving the activation of a heat-shock response that helps the clearance of the aggregates (Boyault et al, 2007b; Kawaguchi et al, 2003). Other components that appear to be essential to aggresome formation include the chaperones CHIP and Hsp, as well as protein kinase CK2 which has recently been shown to regulate HDAC6 activity through phosphorylation (Sha et al, 2009; Watabe and Nakaki, 2011; Zhang and Qian, 2011)
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