Valosin‐containing protein regulates the stability of fused in sarcoma granules in cells by changing ATP concentrations

Abstract

Fused in sarcoma (FUS), a DNA/RNA‐binding protein, undergoes liquid‐liquid phase separation to form granules in cells. Aberrant FUS granulation is associated with neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We found that FUS granules contain a multifunctional AAA ATPase, valosin‐containing protein (VCP), which is known as a key regulator of protein degradation. FUS granule stability depends on ATP concentrations in cells. VCP ATPase changes the FUS granule stability time‐dependently by consuming ATP to reduce its concentrations in the granules: VCPs in de novo FUS granules stabilize the granules, while long‐lasting VCP colocalization destabilizes the granules. The proteolysis‐promoting function of VCP may subsequently dissolve the unstabilized granules. We propose that VCP colocalized to the FUS granules acts as a timer to limit the residence time of the granules in cells.

Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways

“…Our proteomic studies of ORF57 show that this protein binds to TDP-43, as well as other known binders of TDP-43, and regulate TDP-43 proteostasis (43). Some of these proteins, such as SQSTM1 and VCP, are directly involved with clearance of TDP-43 through autophagy and these proteins exhibit mutations associated with TDP-43-opathies (44)(45)(46)(47)(48)(49)(50)(51)(52). Other proteins are chaperones with well documented roles in proteostasis, such as DNAJA1, DNAJC13 and BAG2, and the ubiquitin transferase TRIM25 (53-56).…”