Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

Chu, Siwei; Xie, Xinyi; Payan, Carla; Stochaj, Ursula

doi:10.1186/s13024-023-00639-y

Molecular Neurodegeneration

Table 3 The role of VCP in granulostasis. All comparisons are between controls and the experimental condition listed in the table. Abbreviations: acute, acute stress; CB-5083, reversible competitive inhibitor of VCP [142]; Δ, gene deletion; Eeyarestatin 1, directly binds VCP, preferentially interacts with membrane-associated VCP, inhibits ERAD [218]; MG132, proteasome inhibitor; NA, not applicable; NMS-873, allosteric VCP inhibitor [149]. Cellular models: HEK293, human embryonic kidney epithelial cells; HeLa, human cervix adenocarcinoma, epithelial cells; MEF, mouse embryonic fibroblast; Neuro2a, mouse neuroblastoma cells; U2OS, human osteosarcoma cells, epithelial morphology; S. cerevisiae, budding yeast

From: Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

Experimental condition	SG inducer	Phenotype related to SGs	Model system	Reference
VCP knockdown	heat, acute	impaired SG clearance	HeLa	[159]
VCP knockdown	heat, acute	impaired SG clearance	U2OS	[141]
VCP knockdown	arsenite, acute	impaired SG formation	HeLa	[73]
VCP knockdown	MG132, acute	impaired SG formation	HeLa	[73]
VCP pharmacological inhibition	heat, acute	impaired SG clearance	HeLa	[159]
VCP pharmacological inhibition	arsenite, acute	impaired SG formation	HeLa	[73]
VCP pharmacological inhibition	MG132, acute	impaired SG formation	HeLa	[73]
VCP pharmacological inhibition (Eeyarestatin 1)	heat, acute	impaired SG clearance	U2OS	[141]
VCP pharmacological inhibition (CB-5083)	heat, acute	impaired SG clearance	HeLa	[219]
VCP pharmacological inhibition (CB-5083)	arsenite, acute	impaired SG clearance	HeLa	[219]
VCP pharmacological inhibition (NMS-873)	heat, acute	impaired SG clearance	HeLa	[219]
VCP pharmacological inhibition (NMS-873)	arsenite, acute	impaired SG clearance	HeLa	[219]
VCP pharmacological inhibition (CB-5083)	heat, acute	impaired SG clearance	U2OS	[68]
VCP_R155H knock-in	NA	increased levels of proteins with oxidative damage; levels of G3BP1, eIF2α, p-eIF2α unchanged	VCP_R155H knock-in mouse	[67]
VCP_R155C overexpression	arsenite, acute	reduced localization of VCP in SGs and nucleus	HEK293	[140]
VCP_R155H overexpression	NA	constitutive SGs; SGs contain eIF3 subunits, TDP-43, VCP	HeLa	[159]
VCP_R155H overexpression	heat, acute	no SG clearance defect	C2C12	[67]
VCP_R155H overexpression	heat, acute	impaired SG clearance	U2OS	[74]
VCP_R155H overexpression	arsenite, acute	impaired SG clearance	C2C12	[67]
VCP_R159H overexpression	arsenite, acute	reduced localization of VCP in SGs and nucleus	HEK293	[140]
VCP_A232E overexpression	arsenite, acute	impaired SG clearance	C2C12	[67]
VCP_A232E overexpression	heat, acute	no SG clearance defect	C2C12	[67]
VCP_A232E overexpression	heat, acute	impaired SG clearance	U2OS	[141]
VCP_A232E overexpression	NA	constitutive SGs; SGs contain eIF3 subunits, TDP-43, VCP	HeLa	[159]
VCP_A232E overexpression	heat, acute	impaired SG clearance	U2OS	[74]
VCP wild type overexpression	MG132	VCP and Dorfin colocalize in aggresome	HEK293	[76]
VCP_K524A co-expression with SOD1_G85R	NA	reduced Dorfin-dependent ubiquitination of SOD1_G85R; VCP_K524A does not prevent binding of Dorfin to SOD1_G85R	HEK293, Neuro2a	[76]
UFDL1 knockdown	arsenite, acute	impaired SG formation	HeLa	[73]
UFDL1 knockdown	MG132, acute	impaired SG formation	HeLa	[73]
PLAA knockdown	arsenite, acute	impaired SG formation	HeLa	[73]
PLAA knockdown	MG132, acute	impaired SG formation	HeLa	[73]
ZFAND1 knockdown	heat, acute	SG clearance not impaired, VCP recruitment to SGs not reduced	HeLa	[75]
ZFAND1 knockdown	arsenite, acute	impaired SG clearance, reduced VCP recruitment to SGs	HeLa	[75]
ZFAND1 knockdown	hydrogen peroxide, acute	SG clearance not impaired, VCP recruitment to SGs not reduced	HeLa	[75]
ZFAND1 knockdown	osmotic stress, acute	SG clearance not impaired, VCP recruitment to SGs not reduced	HeLa	[75]
Control; wild type VCP, endogenous levels	heat, acute	VCP-ULK1/2 binding increased; VCP recruited to SGs; ULK1/2 located in SGs	MEF	[141]
ULK1/2 knockdown	arsenite, acute	impaired SG clearance	MEF	[141]
ULK1/2 knockdown	heat, acute	impaired SG clearance	MEF	[141]
ULK1/2 knockdown plus phosphomimetic VCP mutant	heat, acute	SG clearance rescued	MEF	[141]
ULK1/2 pharmacological inhibition	heat, acute	impaired SG clearance	U2OS	[141]
ULK1/2 pharmacological inhibition	arsenite, acute	impaired SG clearance	U2OS	[141]
ULK1/2 pharmacological inhibition	heat, acute	impaired SG clearance	C2C12	[141]
ULK1/2 pharmacological inhibition	arsenite, acute	impaired SG clearance	C2C12	[141]
ULK1/2 agonist	heat, acute	faster SG clearance	U2OS	[141]
VCP knockdown plus ULK1/2 agonist	heat, acute	impaired SG clearance	U2OS	[141]
FAF2 (OPTN) knockdown	heat, acute	impaired SG clearance	U2OS	[74]
G3BP1/2 double knockdown plus ubiquitination deficient G3BP1 mutants	heat, acute	reduced VCP recruitment to SGs	U2OS	[74]
ubx2Δ	NA	SG accumulation	S. cerevisiae	[159]
vms1Δ	NA	SG accumulation	S. cerevisiae	[159]
Cdc48 temperature sensitive allele; non-permissive temperature	NA	SG accumulation	S. cerevisiae	[159]
Ufd1 temperature sensitive allele; non-permissive temperature	NA	SG accumulation	S. cerevisiae	[159]
Npl4 temperature sensitive allele; non-permissive temperature	NA	SG accumulation	S. cerevisiae	[159]

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ISSN: 1750-1326

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