title: Aggresome formation is regulated by RanBPM through an interaction with HDAC6.
abstract: In 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.
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Salemi
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Ahmad W
authors.initials: AW
authors.lastname: Almawi
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Lefebvre
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada cschild-poulter@robarts.ca.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schild-Poulter
keywords: Aggresome; DNA damage; HDAC6; Proteasome inhibition; RanBPM