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AAA ATPase p97/VCP: cellular functions, disease and therapeutic potential.

Vij N - J. Cell. Mol. Med. (2008)

Bottom Line: The interactions of VCP in the endoplasmic reticulum-associated degradation (ERAD) pathway determine the substrate selection for proteasomal degradation.We predict that selective interference of VCP interaction(s) with aberrant protein or its ERAD function will be an effective therapeutic site to rescue functional misfolded protein in diseases like cystic fibrosis and alpha-1-trypsin deficiency.The further functional characterization of VCP and associated proteins in these diseases will help in designing of selective therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Respiratory Sciences & Institute of NanoBioTechnology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. nvij1@jhmi.edu

ABSTRACT
p97/VCP, a member of the AAA-ATPase super family, has been associated with a wide variety of essential cellular protein pathways com prising: (i) nuclear envelope reconstruction, (ii) cell cycle, (iii) Golgi reassembly, (iv) suppression of apoptosis and (v) DNA-damage response [1-6]. In addition, vasolin-containing protein (VCP) dislodges the ubiquitinated proteins from the endoplasmic reticulum (ER) and chaperones them to the cytosol for proteasomal degradation by endoplasmic reticulum-associated degradation (ERAD) [7]. The interactions of VCP in the endoplasmic reticulum-associated degradation (ERAD) pathway determine the substrate selection for proteasomal degradation. Moreover, the interaction with VCP is also required for the ubiquitination of substrate. VCP is phosphorylated by the master cellular kinase, Akt as a mechanism to regulate ERAD [8]. These multiple interactions in protein degradation pathways points to central role of VCP in misfolded protein degradation. VCP has a polyglutamine and ubiquitin-binding capacity and is involved in proteasomal degradation, cytosolic aggregation and processing of polyQ and polyUb aggregates in neurodegenerative and other misfolded protein diseases [9, 10]. Mutations in VCP gene are also linked to a protein deposition disorder, IBMFD [11]. We propose VCP as a therapeutic target for diseases caused by cytosolic protein aggregation or degradation of misfolded protein. We predict that selective interference of VCP interaction(s) with aberrant protein or its ERAD function will be an effective therapeutic site to rescue functional misfolded protein in diseases like cystic fibrosis and alpha-1-trypsin deficiency. The control of VCP expression is also proposed to be a potential therapeutic target in ex-polyQ-induced neurodegenerative diseases [12]. The further functional characterization of VCP and associated proteins in these diseases will help in designing of selective therapeutics.

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Related in: MedlinePlus

Summary of misfolded protein disorders. Misfolded protein disorders can be divided into two categories based on (1) loss of misfolded protein by ubiquitin proteasome system (UPS) or endoplasmic reticulum-associated degradation (ERAD) or (2) aggregation of misfolded protein in cytosol (aggresomes) or ER (Russell bodies). Misfolded protein associated with the disease are shown in bracket.
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fig02: Summary of misfolded protein disorders. Misfolded protein disorders can be divided into two categories based on (1) loss of misfolded protein by ubiquitin proteasome system (UPS) or endoplasmic reticulum-associated degradation (ERAD) or (2) aggregation of misfolded protein in cytosol (aggresomes) or ER (Russell bodies). Misfolded protein associated with the disease are shown in bracket.

Mentions: We would like to point out here that misfolded protein disorders are of two types: (i) loss of functional protein by ubiquitin-proteasome-mediated ERAD and (ii) aggregation of misfolded protein in cystosol (aggresomes) or ER (Russel bodies). The misfolded protein disorders that fall under these two categories are summarized in Fig.2. In most of the misfolded protein disorders in first category, protein rescued from proteasomal degradation are functional and can rescue the disease pathophysiology. One approach is to use proteasome inhibitors but that result in cytosolic aggregates (aggresomes) as shown in Fig.1. Several chemical chaperones have been tested in these diseases to both avoid degradation and aggregation of misfolded protein (Table 1) but none of them could be developed as an effective therapeutic strategy due to their inability to interact specifically with the molecular targets. We propose here that identification and therapeutic targeting of molecular chaperones like VCP is a selective alternate approach. The selective interference of VCP interaction with aberrant protein or lkB can be developed as a therapeutic approach to not only rescue functional misfolded protein but also inhibiting chronic kB-NFKB-mediated inflammatory signalling.


AAA ATPase p97/VCP: cellular functions, disease and therapeutic potential.

Vij N - J. Cell. Mol. Med. (2008)

Summary of misfolded protein disorders. Misfolded protein disorders can be divided into two categories based on (1) loss of misfolded protein by ubiquitin proteasome system (UPS) or endoplasmic reticulum-associated degradation (ERAD) or (2) aggregation of misfolded protein in cytosol (aggresomes) or ER (Russell bodies). Misfolded protein associated with the disease are shown in bracket.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4514128&req=5

fig02: Summary of misfolded protein disorders. Misfolded protein disorders can be divided into two categories based on (1) loss of misfolded protein by ubiquitin proteasome system (UPS) or endoplasmic reticulum-associated degradation (ERAD) or (2) aggregation of misfolded protein in cytosol (aggresomes) or ER (Russell bodies). Misfolded protein associated with the disease are shown in bracket.
Mentions: We would like to point out here that misfolded protein disorders are of two types: (i) loss of functional protein by ubiquitin-proteasome-mediated ERAD and (ii) aggregation of misfolded protein in cystosol (aggresomes) or ER (Russel bodies). The misfolded protein disorders that fall under these two categories are summarized in Fig.2. In most of the misfolded protein disorders in first category, protein rescued from proteasomal degradation are functional and can rescue the disease pathophysiology. One approach is to use proteasome inhibitors but that result in cytosolic aggregates (aggresomes) as shown in Fig.1. Several chemical chaperones have been tested in these diseases to both avoid degradation and aggregation of misfolded protein (Table 1) but none of them could be developed as an effective therapeutic strategy due to their inability to interact specifically with the molecular targets. We propose here that identification and therapeutic targeting of molecular chaperones like VCP is a selective alternate approach. The selective interference of VCP interaction with aberrant protein or lkB can be developed as a therapeutic approach to not only rescue functional misfolded protein but also inhibiting chronic kB-NFKB-mediated inflammatory signalling.

Bottom Line: The interactions of VCP in the endoplasmic reticulum-associated degradation (ERAD) pathway determine the substrate selection for proteasomal degradation.We predict that selective interference of VCP interaction(s) with aberrant protein or its ERAD function will be an effective therapeutic site to rescue functional misfolded protein in diseases like cystic fibrosis and alpha-1-trypsin deficiency.The further functional characterization of VCP and associated proteins in these diseases will help in designing of selective therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Respiratory Sciences & Institute of NanoBioTechnology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. nvij1@jhmi.edu

ABSTRACT
p97/VCP, a member of the AAA-ATPase super family, has been associated with a wide variety of essential cellular protein pathways com prising: (i) nuclear envelope reconstruction, (ii) cell cycle, (iii) Golgi reassembly, (iv) suppression of apoptosis and (v) DNA-damage response [1-6]. In addition, vasolin-containing protein (VCP) dislodges the ubiquitinated proteins from the endoplasmic reticulum (ER) and chaperones them to the cytosol for proteasomal degradation by endoplasmic reticulum-associated degradation (ERAD) [7]. The interactions of VCP in the endoplasmic reticulum-associated degradation (ERAD) pathway determine the substrate selection for proteasomal degradation. Moreover, the interaction with VCP is also required for the ubiquitination of substrate. VCP is phosphorylated by the master cellular kinase, Akt as a mechanism to regulate ERAD [8]. These multiple interactions in protein degradation pathways points to central role of VCP in misfolded protein degradation. VCP has a polyglutamine and ubiquitin-binding capacity and is involved in proteasomal degradation, cytosolic aggregation and processing of polyQ and polyUb aggregates in neurodegenerative and other misfolded protein diseases [9, 10]. Mutations in VCP gene are also linked to a protein deposition disorder, IBMFD [11]. We propose VCP as a therapeutic target for diseases caused by cytosolic protein aggregation or degradation of misfolded protein. We predict that selective interference of VCP interaction(s) with aberrant protein or its ERAD function will be an effective therapeutic site to rescue functional misfolded protein in diseases like cystic fibrosis and alpha-1-trypsin deficiency. The control of VCP expression is also proposed to be a potential therapeutic target in ex-polyQ-induced neurodegenerative diseases [12]. The further functional characterization of VCP and associated proteins in these diseases will help in designing of selective therapeutics.

Show MeSH
Related in: MedlinePlus