International Journal of Molecular Sciences Review Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases Xiaonan Sun and Hongyu Qiu * Center of Molecular and Translational Medicine, Institution of Biomedical Science, Georgia State University, Atlanta, GA 30303, USA; [email protected] * Correspondence: [email protected]; Tel.: +404-413-3371; Fax: +404-413-9566 Received: 9 May 2020; Accepted: 26 May 2020; Published: 28 May 2020 Abstract: Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved in both ER and mitochondrial function. Impairment of VCP, caused by structural mutations or alterations of expressions, contributes to the development of various diseases, through an integrating effect on ER, mitochondria and the ubiquitin–proteasome system, by interfering with protein degradation, subcellular translocation and calcium homeostasis. Thus, understanding the role and the molecular mechanisms of VCP in these organelles brings new insights to the pathogenesis of the associated diseases, and leads to the discovery of new therapeutic strategies. In this review, we summarized the progress of studies on VCP, in terms of its regulation of ER and mitochondrial function and its implications for the associated diseases, focusing on the cancers, heart disease, and neurodegenerative disorders. Keywords: endoplasmic reticulum; mitochondria; valosin-containing protein; calcium homeostasis; disease 1. Introduction The endoplasmic reticulum (ER) is one of the largest membrane organelles in cells, and plays an important role in protein synthesis, protein folding and quality control, lipid metabolism and Ca2+ homeostasis [1]. As ER is found in all cell types, the sarcoplasmic reticulum (SR), a morphologically distinct version of the ER, only exits in muscle cells that are specialized for Ca2+ release to fuel muscle contraction. SR consists of two spatial and functional organizations, termed longitudinal SR and junctional SR, tasked with the release and the uptake of Ca2+, ensuring delivery of Ca2+ for contraction to occur [2–4]. ER dysfunction has been associated with cellular dysfunction and cell death [5]. ER contains multiple domains, among which the biggest is a bilayer barrier around the cell nucleus, named the nuclear envelope. In addition, the peripheral ER membrane extends from the nuclear envelope to the whole cytoplasm, forming interactions with other organelles and contacting the plasma membrane [6]. One of the most essential organelles that the ER interacts with is the mitochondria, which are responsible for regulating Ca2+ homeostasis, apoptosis and ATP production. The dysfunction of mitochondria leads to impaired energy production and contributes to the pathogenesis of many metabolic diseases [7,8]. Most recent evidence has demonstrated that mitochondria communicate with the ER via mitochondria-associated ER membranes (MAMs) [8,9]. Although increasing evidence demonstrates that impaired function of the ER and mitochondria is associated with the pathogenesis of a variety of diseases, including cancers, neurodegeneration diseases Int. J. Mol. Sci. 2020, 21, 3842; doi:10.3390/ijms21113842 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020 , 21, x FOR PEER REVIEW 2 of 13 Int. J. Mol. Sci. 2020, 21, 3842 2 of 13 diseases and heart disease, as well as metabolic diseases such as obesity and diabetes [9–11], the underlyingand heart disease, mechanisms as well remain as metabolic largely unknown. diseases such as obesity and diabetes [9–11], the underlying mechanismsThe valosin-containing remain largely unknown.protein (VCP), also known as p97 in mammals, Cdc48 in yeast and plants,The CDC-48 valosin-containing in worms and protein Ter94 (VCP), in flies, also was known initially as p97 recognized in mammals, as one Cdc48 of inthe yeast ER-associated and plants, proteins,CDC-48 in and worms has and been Ter94in demonstrated flies, was initiallyas playing recognized critical as roles one of in the regulating ER-associated ER proteins,formation and and has morphologybeen demonstrated by participating as playing criticalin the roles ubiquitin–protea in regulating ERsome formation system and (UPS) morphology and other by intracellular participating signalingin the ubiquitin–proteasome pathways [12,13]. One system of the (UPS) key and function others intracellular of VCP is to signaling conjugate pathways its substrates [12,13 with]. One the of ubiquitinthe key functions chain through of VCP interaction is to conjugate with its a substratesvariety of withubiquitin the ubiquitin adapters, chain and throughthen transport interaction the substrateswith a variety to the of ubiquitin26S proteasome adapters, for and subsequent then transport degradation, the substrates such toas theER-associated 26S proteasome protein for degradationsubsequent degradation,(ERAD) [13]. such The asmutations ER-associated of VCP protein are f degradationound to be (ERAD)associated [13 with]. The some mutations human of degenerativeVCP are found disorders, to be associated such as withamyotrophic some human lateral degenerative sclerosis (ALS), disorders, inclusion such body as amyotrophic myopathy (IBM) lateral associatedsclerosis (ALS), with inclusionPaget disease body of myopathy the bone (IBM) (PDB), associated and frontotemporal with Paget disease dementia of the (FTD), bone also (PDB), called and IBMPFD,frontotemporal which dementiamainly affect (FTD), the also brain called and IBMPFD,muscles [12]. which In mainlyaddition, aff theect theVCP brain expression and muscles level was [12]. alsoIn addition, shown to the be VCPupregulated expression in some level cancers, was also mainl showny in toresponse be upregulated to the increased in some burden cancers, of protein mainly degradation,in response to indicating the increased that burdenVCP inhibition of protein could degradation, be a promising indicating therapeutic that VCP approach inhibition to could cancer be managementa promising therapeutic[13–15]. Furthermore, approach torecent cancer studies management also found [13 that–15 VCP]. Furthermore, participates recent in cardiomyocyte studies also growthfound that and VCP survival, participates and plays in cardiomyocyte a protective growthrole against and survival,the stress-induced and plays apathogenesis protective role in against heart diseasesthe stress-induced by attenuating pathogenesis mitochondrial in heart and diseases ER stress by attenuating through regulating mitochondrial calcium and homeostasis ER stress through [16– 19].regulating calcium homeostasis [16–19]. InIn this this review, review, we we summarized summarized the the new new progress progress achi achievedeved in in studies studies of of VCP, VCP, regarding regarding its its regulatingregulating eeffectffect onon ER ER and and mitochondria mitochondria functions, functions, and itsand implications its implications for various for various diseases, diseases, focusing focusingon cancer, on heart cancer, disease heart and disease neurodegenerative and neurodegenera disorders.tive disorders. 2.2. The The Structure Structure and and Distribution Distribution of of VCP VCP in in Mammal Mammal Cells Cells VCPVCP belongs belongs to to the the type type II II class class of of the the AAA AAA (ATPase (ATPasess Associated Associated with with various various cellular cellular Activities) Activities) ATPaseATPase family family [20]. [20]. As As shown shown in in Figure Figure 11,, VCPVCP possessespossesses fourfour structuralstructural domains,domains, includingincluding aa conservedconserved N-terminal N-terminal domain, domain, two two AAA AAA ATPase ATPase domains (D1 and D2), and a C-terminal C-terminal tail. D1 D1 and and D2D2 domains domains are are stacked stacked in in a a head-to-tail head-to-tail manner manner and and connect connect with with a a short short polypeptide polypeptide linker, linker, while while thethe N-terminal N-terminal domain domain is is connected connected to to the the D1 D1 domain domain by by another another short short linker. linker. In In mammalian mammalian cells, cells, VCPVCP functions functions as as a a homohexamer homohexamer [20]. [20]. The The active active for formm of of VCP VCP is is a a complex complex of of a adouble double ring ring structure, structure, withwith the the D1 D1 and and D2 D2 domains domains sitting on top of each o other.ther. Figure 1. The scheme of the mammalian isoform of VCP domains and their function. VCP is constituted Figureby one binding1. The domainscheme N-domain,of the mammalian two ATPase isoform domains of (D1VCP domain domains and D2and domain) their function. and a C-terminus. VCP is constitutedN-domains by are one responsible binding domain for substrate N-domain, recognition two ATP andase binding. domains The (D1 D2domain domain and contributes D2 domain) to andthe a major C-terminus. ATPase N-domains activity of are VCP, responsible while the for D1 sub domainstrate recognition is responsible and forbinding. the assembly The D2 domain of VCP contributeshomohexamer. to the The major N-domain ATPase andactivity D1domain of VCP, arewh connectedile the D1 domain by an N-D1 is responsible linker, and for the the D1 assembly and D2 ofdomains VCP homohexamer. are connected The by