Valosin-containing protein is a key mediator between autophagic cell death and apoptosis in adult hippocampal neural stem cells following insulin withdrawal

Abstract

BackgroundProgrammed cell death (PCD) plays essential roles in the regulation of survival and function of neural stem cells (NSCs). Abnormal regulation of this process is associated with developmental and degenerative neuronal disorders. However, the mechanisms underlying the PCD of NSCs remain largely unknown. Understanding the mechanisms of PCD in NSCs is crucial for exploring therapeutic strategies for the treatment of neurodegenerative diseases.ResultWe have previously reported that adult rat hippocampal neural stem (HCN) cells undergo autophagic cell death (ACD) following insulin withdrawal without apoptotic signs despite their normal apoptotic capabilities. It is unknown how interconnection between ACD and apoptosis is mediated in HCN cells. Valosin-containing protein (VCP) is known to be essential for autophagosome maturation in mammalian cells. VCP is abundantly expressed in HCN cells compared to hippocampal tissue and neurons. Pharmacological and genetic inhibition of VCP at basal state in the presence of insulin modestly impaired autophagic flux, consistent with its known role in autophagosome maturation. Of note, VCP inaction in insulin-deprived HCN cells significantly decreased ACD and down-regulated autophagy initiation signals with robust induction of apoptosis. Overall autophagy level was also substantially reduced, suggesting the novel roles of VCP at initial step of autophagy.ConclusionTaken together, these data demonstrate that VCP may play an essential role in the initiation of autophagy and mediation of crosstalk between ACD and apoptosis in HCN cells when autophagy level is high upon insulin withdrawal. This is the first report on the role of VCP in regulation of NSC cell death. Elucidating the mechanism by which VCP regulates the crosstalk of ACD and apoptosis will contribute to understanding the molecular mechanism of PCD in NSCs.

Valosin-containing protein (VCP): structure, functions, and implications in neurodegenerative diseases

“…Adult hippocampal neural stem (HCN) cells undergo ACD following insulin withdrawal despite their intact apoptotic capability (Yu et al 2008). At the basal level of autophagy in the presence of insulin, VCP inactivation impaired autophagosome maturation, consistent with the previous reports on the involvement of VCP in autophagosome maturation at the late stage of autophagy process (Yeo et al 2016). On the other hand, in insulin-deprived HCN cells, which have a high autophagy rate, VCP depletion or inhibition decreased autophagy initiation and concomitantly suppressed ACD.…”

“…On the other hand, in insulin-deprived HCN cells, which have a high autophagy rate, VCP depletion or inhibition decreased autophagy initiation and concomitantly suppressed ACD. However, ACD suppression did not reduce cell death, since the cell death mode was switched to apoptosis (Yeo et al 2016). These results suggest that VCP may be involved in distinct stages (e.g.…”

“…We reported that VCP plays an essential role in the initiation of autophagy or maturation of autophagosomes, depending on the autophagy level (Yeo et al 2016). Adult hippocampal neural stem (HCN) cells undergo ACD following insulin withdrawal despite their intact apoptotic capability (Yu et al 2008).…”

Autophagy-dependent cell death – where, how and why a cell eats itself to death

“…Normally, VCP is required for the proper maturation of autophagosomes into degradative autolysosomes (Ju et al, 2009); VCP inhibition during basal autophagy leads to accumulation of the lipidated membrane-associated form of LC3 (LC3-II; see Box 1), similar to inhibition of lysosomal function. However, knockdown or inhibition of VCP in insulin-deprived HCN cells led to a reduction in LC3-II, even in the presence of lysosomal inhibitors, and attenuated the formation of DFCP1 puncta (a biomarker for the accumulation of PI3P at the membrane), suggesting that VCP is necessary for an early stage of autophagosome initiation in this system (Yeo et al, 2016). Interestingly, the Drosophila VCP, TER94, has been previously linked to autophagy-dependent developmental cell death of the larval midgut (see Box 2) (Santhanam et al, 2014).…”

“…However, it is not known how either an increase in cellular Ca 2+ or active GSK-3β links to lethal autophagy. Further investigations have implicated valosincontaining protein (VCP) as a factor that differentiates lethal autophagy from survival autophagy (Yeo et al, 2016). VCP is a multi-function hexameric AAA ATPase that is involved in the remodeling of its ubiquitylated client proteins to facilitate their extraction from membranes or protein complexes.…”