IBMPFD Disease-Causing Mutant VCP/p97 Proteins Are Targets of Autophagic-Lysosomal Degradation

Abstract

The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget’s Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone. We showed that, unlike commonly studied R155C or R191Q mutants, the P137L mutant protein stimulated both autophagosome and autolysosome formation. Moreover, P137L mutant protein itself was a substrate of autophagy. Starvation- and mTOR inhibition-induced autophagy led to the degradation of the P137L mutant protein, while preserving the wild-type and functional VCP/p97. Strikingly, similar to the P137L mutant, other IBMPFD-related VCP/p97 mutants, namely R93C and G157R mutants induced autophagosome and autolysosome formation; and G157R mutant formed aggregates that could be cleared by autophagy. Therefore, cellular phenotypes caused by P137L mutant expression were not isolated observations, and some other IBMPFD disease-related VCP/p97 mutations could lead to similar outcomes. Our results indicate that cellular mechanisms leading to IBMPFD disease may be various, and underline the importance of studying different disease-associated mutations in order to better understand human pathologies and tailor mutation-specific treatment strategies.

Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD

“…2e ). This robust effect of p97 inhibition on NPC1 levels likely reflected its critical role in both ERAD and autophagy 23 – 25 .…”

The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

“…Autophagy inhibition causes accumulation of the complex consisting of p62 and protein aggregates, which results in the delayed migration of ubiquitinated substrates to the proteasomes (52). In addition to the failure of transport of proper ubiquitinated protein targets and so resultant positional isolation, abnormal p62 aggregates can also functionally inactivate the regulators of the UPS, such as the p97/VCP (64). In this process, the binding between the PB1 domain and UBA domain of p62 and the proteasome regulator is critically required.…”

Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy

“…Autophagic inhibition causes the accumulation of protein aggregates in complex with p62, which, in turn, sequester ubiquitinated substrates from proteasomal degradation. In addition to sequestering proteasomal substrates, aberrant p62-containing aggregates may also recruit and, thus, functionally inactivate the regulators of the UPS such as p97/VCP ( Bayraktar et al, 2016 ). This recruitment may be facilitated by specific interactions with the PB1 or UBA domain of p62, potentiating the widespread disruption of proteasomal flux.…”