IBMPFD disease-causing mutant VCP/p97 proteins are targets of autophagic-lysosomal degradation

Bayraktar, Öznur and Oral, Özlem and Kocatürk, Nur Mehpare and Akkoç, Yunus and Eberhart, Karin and Koşar, Ali and Gözüaçık, Devrim (2016) IBMPFD disease-causing mutant VCP/p97 proteins are targets of autophagic-lysosomal degradation. PLoS One, 11 (10). ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0164864


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.

Item Type:Article
Subjects:Q Science > Q Science (General)
R Medicine > R Medicine (General)
R Medicine > RB Pathology
ID Code:31000
Deposited By:Devrim Gözüaçık
Deposited On:02 Dec 2016 15:54
Last Modified:22 May 2019 13:45

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