FACL4, a New Gene Encoding Long-Chain Acyl-CoA Synthetase 4, Is Deleted in a Family with Alport Syndrome, Elliptocytosis, and Mental Retardation

Piccini, Monica; Vitelli, Francesca; Bruttini, Mirella; Pober, Barbara R.; Jónsson, Jón J.; Villanova, Marcello; Zollo, Massimo; Borsani, Giuseppe; Ballabio, Andrea; Renieri, Alessandra

doi:10.1006/geno.1997.5104

Cited by 110 publications

(77 citation statements)

References 34 publications

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“…These physical associations have pivotal roles in numerous cellular functions including Ca 2þ signaling, lipid transport, energy metabolism, and cell survival. The ER-contiguous membranes also contain multiple phospholipids and glycosphingolipid synthesizing enzymes including long chain fatty acid-CoA ligase type 4 (FACl4) and phosphatidylserine synthase-1(PSS-1), and support direct transfer of lipids between the ER and mitochondria (Piccini et al 1998;Stone and Vance 2000). The interaction between the two organelles is mediated by mitochondrial shaping proteins and key chaperones including calnexin, calreticulin, ERp44, ERp57, grp75, and the sigma-1 receptor.…”

Section: Er-mitochondria Interactionsmentioning

confidence: 99%

ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

Malhotra

Kaufman

2011

Cold Spring Harbor Perspectives in Biology

299

268

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The endoplasmic reticulum (ER) is the primary site for synthesis and folding of secreted and membrane-bound proteins. Proteins are translocated into ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to assist in proper folding. Properly folded proteins traffic from the ER to the Golgi apparatus; misfolded proteins are targeted to degradation. Unfolded protein response (UPR) is a highly regulated intracellular signaling pathway that prevents accumulation of misfolded proteins in the ER lumen. UPR provides an adaptive mechanism by which cells can augment protein folding and processing capacities of the ER. If protein misfolding is not resolved, the UPR triggers apoptotic cascades. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintain cellular homeostasis and determine cell fate under various pathophysiological conditions. Regulated Ca 2þ transfer from the ER to the mitochondria is important in maintaining control of prosurvival/prodeath pathways. We discuss the signaling/communication between the ER and mitochondria and focus on the role of the mitochondrial permeability transition pore in these complex processes.T he ER is an elaborate membranous network present in all eukaryotic cells and responsible for many homeostatic responses that include folding and maturation of newly synthesized secretory and transmembrane proteins (Kleizen and Braakman 2004). In addition, this organelle is also the site of cholesterol and steroid biosynthesis, lipid biosynthesis, assembly of core-asparagine linked oligosaccharides, and membrane and secreted protein biosynthesis. Newly synthesized proteins require proper folding within the ER lumen prior to trafficking to specific destinations in the cell. These cellular processes are initiated when nascent polypeptide chains emerge in ER lumen, where posttranslational modifications such as N-linked glycosylation, and intra-and intermolecular disulfide bond formation facilitate the folding of polypeptides to form specific tertiary and quaternary structures for proper protein function (Molinari 2007). Although the amino acid sequence of the protein determines many

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Section: Er-mitochondria Interactionsmentioning

confidence: 99%

ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

Malhotra

Kaufman

2011

Cold Spring Harbor Perspectives in Biology

299

268

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“…Despite the presence of other ACSL isoforms in brain, human ACSL4 is associated with depression [75] and mutations in the human Acsl4 gene that decrease 20:4-CoA synthetase activity cause a form of X-linked mental retardation [76][77][78]. The effect of these mutations suggests that ACSL4 is critical for normal brain function, perhaps related to its preference for long-chain polyunsaturated FAs [35], which are enriched in brain phospholipids.…”

Section: Acyl-coa Synthetases In Pathological Conditionsmentioning

confidence: 99%

“…Although the causality between the change of ACSL isoforms and specific diseases has not been established, these observations indicate that ACSL isoforms are linked to metabolic changes or FA demand under several pathological conditions. For example, in patients with inflammatory bowel disease, the increase of Acsl1 and Acsl4 mRNA in the terminal ileum and colon might provide acyl-CoAs for the synthesis of phospholipids; these can serve as precursors for inflammatory mediators or support membrane integrity of the affected intestine [74].Despite the presence of other ACSL isoforms in brain, human ACSL4 is associated with depression [75] and mutations in the human Acsl4 gene that decrease 20:4-CoA synthetase activity cause a form of X-linked mental retardation [76][77][78]. The effect of these mutations suggests that ACSL4 is critical for normal brain function, perhaps related to its preference for long-chain polyunsaturated FAs [35], which are enriched in brain phospholipids.…”

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confidence: 99%

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

2007

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Thirteen homologous proteins comprise the long-chain acyl-CoA synthetase (ACSL), fatty acid transport protein (FATP), and bubblegum (ACSBG) subfamilies that activate long-chain and verylong-chain fatty acids to form acyl-CoAs. Gain-and loss-of-function studies show marked differences in the ability of these enzymes to channel fatty acids into different pathways of complex lipid synthesis. Further, the ability of the ACSLs and FATPs to enhance cellular FA uptake does not always require these proteins to be present on the plasma membrane; instead, FA uptake can be increased by enhancing its conversion to acyl-CoA and its metabolism in downstream pathways. Since altered fatty acid metabolism is a hallmark of numerous metabolic diseases and pathological conditions, the ACSL, FATP and ACSBG isoforms are likely to play important roles in disease etiology. A family of acyl-CoA synthetases activates intracellular long-chain fatty acidsBefore a fatty acid (FA) from an exogenous or endogenous source can enter any metabolic pathway with the exception of eicosanoid metabolism, it must first be activated to form an acyl-CoA. This activation step is catalyzed by acyl-CoA synthetase (ACS) via a two-step reaction: 1) the formation of an intermediate fatty acyl-AMP with the release of pyrophosphate, and 2) the formation of a fatty acyl-CoA with the release of AMP.The ACS family is comprised of at least 25 members [1]. Although overlap exists, ACS family members are broadly classified by their substrate specificities for FAs of varying chain length. This review will focus on the three subfamilies of ACS enzymes that activate long-chain and/ or very-long-chain saturated and unsaturated FAs, long-chain ACSs (ACSL), very-long-chain ACSs (FATP), and bubblegum (ACSBG) isoforms [2].The ACSL, FATP and ACSBG families include multiple isoforms, each encoded by a separate gene (Tables 1, 2). Additionally, splice variants of ACSL isoforms have been identified in both humans and rodents [3]. ACS enzymes share significant amino acid sequence similarity, particularly in two highly conserved regions, a putative ATP-AMP signature motif for ATP binding and a motif for FA binding [4]. Despite these similarities, purified ACSL and FATP isoforms and their splice variants show distinct enzyme kinetics, differences in sensitivity to inhibitors ( Role of acyl-CoA synthetases in FA channelingThe existence of 13 ACSL, FATP and ACSBG isoforms that all activate long-chain FA has suggested that each has an independent role in channeling FA within cells. Unique roles for ACS isoforms were first identified in studies of Saccharomyces cerevisiae mutants that lacked the ACS isoforms Faa1 and Faa4, and were unable to use exogenously provided fatty acids [31]. Similarly, complementation studies of ACS-deficient E. coli showed that each of the 5 rat ACSL isoforms differs in its ability to channel FA into specific pathways like phospholipid synthesis and β-oxidation [32]. The ACSL and FATP isoforms also differ in their ability to complement FA uptake and a...

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“…34,35 In addition to the function in phospholipid homeostasis, MAMs have been implicated in the metabolism of cholesterol 36,37 and its metabolites and in the trafficking of sphingolipids. 38 MAMs have also an important role in ER-mitochondrial calcium (Ca 2 þ ) transfer.…”

Section: Fasmentioning

confidence: 99%

The role of PML in the control of apoptotic cell fate: a new key player at ER–mitochondria sites

2011

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The development of malignant tumors results from deregulated proliferation or an inability of cells to undergo apoptotic cell death. Experimental works of the past decade have highlighted the importance of calcium (Ca 2 þ ) in the regulation of apoptosis. Several studies indicate that the Ca 2 þ content of the endoplasmic reticulum (ER) determines the cell's sensitivity to apoptotic stress and perturbation of ER Ca 2 þ homeostasis appears to be a key component in the development of several pathological situations. Sensitivity to apoptosis depends on the ability of cells to transfer Ca 2 þ from the ER to the mitochondria. The physical platform for the interplay between the ER and mitochondria is a domain of the ER called the mitochondria-associated membranes (MAMs). The disruption of these contact sites has profound consequences for cellular function, such as imbalances of intracellular Ca 2 þ signaling, cellular stress, and disrupted apoptosis progression. The promyelocytic leukemia (PML) protein has been previously recognized as a critical and essential regulator of multiple apoptotic response. Nevertheless, how PML would exert such broad and fundamental role in apoptosis remained for long time a mystery. In this review, we will discuss how recent results demonstrate that the elusive mechanism whereby the PML tumor suppressor exerts its essential role in apoptosis triggered by Ca 2 þ -dependent stimuli can be attributed to its unexpected and fundamental role at MAMs in the control of the functional cross-talk between ER and mitochondria. The Promyelocytic Leukemia ProteinThe promyelocytic leukemia (PML) protein is a tumor suppressor gene originally identified at the break point of the t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL), a distinct subtype of acute myeloid leukemia. As a consequence of this translocation, PML fuses to the retinoic acid (RA) receptor alpha (RARa) gene. Two fusion genes are generated encoding PML-RARa and RARa-PML fusion proteins, which coexist in the leukemic cells, blocking heamatopoietic differentiation (for a review, see Pandolfi; 1 Salomoni and Pandolfi. 2 PML has, therefore, become the object of intense research on the basis of this premise. Since then, PML has been shown to regulate diverse cellular functions, such as transcriptional regulation, DNA-damage response, sumoylation process, cellular senescence, neoangiogenesis, and, of relevance to this review, apoptosis. 3,4 PML belongs to a large family of proteins harboring a tripartite structure that contains a zinc-finger called the RING motif (R) located N-terminally followed by two additional zincfingers motifs (B-boxes; B) and an a-helical coiled-coil domain (CC), collectively referred to as the RBCC domain. The RBCC domain mediates protein-protein interactions and is responsible for PML multimerization and the formation of macromolecular complexes. The C-terminal region of PML is less structured and varies between PML isoforms. Alternative splicing of C-terminal exons is responsible for the existen...

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FACL4, a New Gene Encoding Long-Chain Acyl-CoA Synthetase 4, Is Deleted in a Family with Alport Syndrome, Elliptocytosis, and Mental Retardation

Cited by 110 publications

References 34 publications

ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

ER Stress and Its Functional Link to Mitochondria: Role in Cell Survival and Death

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

The role of PML in the control of apoptotic cell fate: a new key player at ER–mitochondria sites

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