title: 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.
authors: Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Istanbul, 34956, Turkey.
authors: Oznur
authors: O
authors: Bayraktar
authors: Sabanci University, Nanotechnology Research and Application Center, Istanbul, 34956, Turkey.
authors: Ozlem
authors: O
authors: Oral
authors: Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Istanbul, 34956, Turkey.
authors: Nur Mehpare
authors: NM
authors: Kocaturk
authors: Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Istanbul, 34956, Turkey.
authors: Yunus
authors: Y
authors: Akkoc
authors: Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Istanbul, 34956, Turkey.
authors: Karin
authors: K
authors: Eberhart
authors: Sabanci University, Faculty of Engineering and Natural Sciences, Mechatronics Engineering Program, Istanbul, 34956, Turkey.|Sabanci University, Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Istanbul, 34956, Turkey.
authors: Ali
authors: A
authors: Kosar
authors: Sabanci University, Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Istanbul, 34956, Turkey.|Sabanci University, Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Istanbul, 34956, Turkey.
authors: Devrim
authors: D
authors: Gozuacik
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D057180:Frontotemporal Dementia / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000235:genetics*; D010001:Osteitis Deformans / Q000235:genetics*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse