Aggresome formation is regulated by RanBPM through an interaction with HDAC6

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Degradation

Background:

• Proteasomal impairment leads to the accumulation of damaged proteins, forming aggresomes.
• Aggresome formation involves protein transport along microtubules and depends on histone deacetylase 6 (HDAC6).
• The role of Ran-Binding Protein M (RanBPM) in aggresome formation is not well understood.

Purpose of the Study:

• To investigate the role of RanBPM in aggresome formation.
• To elucidate the mechanism by which RanBPM influences aggresome biogenesis.

Main Methods:

• Immunofluorescence microscopy to observe protein localization.
• Cellular treatments with ionizing radiation, MG132, and etoposide.
• RNA interference (shRNA) to deplete RanBPM.
• Co-immunoprecipitation and in vitro assays to study protein interactions and enzyme activity.

Main Results:

• RanBPM relocalizes to perinuclear aggresomes upon cellular stress, co-localizing with ubiquitin, dynein, and HDAC6.
• RanBPM depletion impairs aggresome formation mediated by HDAC6.
• RanBPM directly interacts with HDAC6, inhibiting its deacetylase activity via the LisH/CTLH domain.

Conclusions:

• RanBPM is a crucial regulator of aggresome formation.
• RanBPM modulates HDAC6 activity, thereby controlling the cellular response to protein aggregation.
• RanBPM acts as a central component in the aggresome biogenesis pathway.