LYCAT, a homologue of C. elegans acl-8,acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice

Imae, Rieko; Inoué, Takao; Nakasaki, Yasuko; Uchida, Yoshishige; Ohba, Yohsuke; Kono, Nozomu; Nakanishi, Hiroki; Sasaki, Takehiko; Mitani, Shohei; Arai, Hiroyuki

doi:10.1194/jlr.m018655

Cited by 57 publications

(89 citation statements)

References 31 publications

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“…A similar study (59) presented a drop not only of the PI content but also of the PIP2 content in the liver and brain of mice deficient in the LPIAT1 gene. First characterized in yeast (12), the stearic acid enrichment of PI has been studied in worms (60) and mice (61). Similar to Psi1p in yeast, the three Caenorhabditis elegans acyltransferases ACL-8, -9, and -10 and LYCAT, its closest homologue in the mouse, have been found to direct stearic acid into the sn-1 position of PI.…”

Section: Discussionmentioning

confidence: 99%

Requirement of Phosphoinositides Containing Stearic Acid To Control Cell Polarity

Doignon

Laquel

Testet

et al. 2016

Molecular and Cellular Biology

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c Phosphoinositides (PIPs) are present in very small amounts but are essential for cell signaling, morphogenesis, and polarity. By mass spectrometry, we demonstrated that some PIPs with stearic acyl chains were strongly disturbed in a psi1⌬ Saccharomyces cerevisiae yeast strain deficient in the specific incorporation of a stearoyl chain at the sn-1 position of phosphatidylinositol. The absence of PIPs containing stearic acid induced disturbances in intracellular trafficking, although the total amount of PIPs was not diminished. Changes in PIPs also induced alterations in the budding pattern and defects in actin cytoskeleton organization (cables and patches). Moreover, when the PSI1 gene was impaired, a high proportion of cells with bipolar cortical actin patches that occurred concomitantly with the bipolar localization of Cdc42p was specifically found among diploid cells. This bipolar cortical actin phenotype, never previously described, was also detected in a bud9⌬/bud9⌬ strain. Very interestingly, overexpression of PSI1 reversed this phenotype. Lipids are not limited to the simple role of being components of biological membranes for cell compartmentalization. On the basis of their structural diversity, they are also biologically active molecules regulating several important physiological functions. Lipids can be classified into eight broad categories, on the basis of well-defined chemical and biochemical principles, with distinct functions in cells (1). Among them, phosphatidylinositol-4-phosphate [PI(4)P] and phosphatidylinositol-4,5-diphosphate [PI(4,5)P 2 ], derived from phosphatidylinositol (PI) by a series of kinase reactions, play major roles, even though they are minor constituents of cellular membranes; e.g., in the yeast Saccharomyces cerevisiae, PI represents about 20% of total phospholipids (2) and phosphatidylinositol phosphates (PIPs) represent only 0.1 to 1.1% of PIs (3, 4). It has been established that some mutations in genes encoding PIP-metabolizing enzymes are responsible for human diseases (Lowe syndrome, myopathy, Charcot-Marie-Tooth disease, psychiatric diseases, diabetes, cancer, Alzheimer's disease, etc.) (5). In addition, previous studies have demonstrated the role of PIPs in the control of cell polarity (by acting on actin cytoskeleton dynamics), secretory pathways, and septin recruitment and organization in animals, plants, and yeasts (6-11). Nevertheless, most studies pointing out a specific role for PIPs are related to the polar head groups and not to the fatty acid component, even though PIs from plants, animals, and yeast contain larger amounts of saturated fatty acids than other phospholipids (12). Only a few studies have highlighted the importance of the acyl chain composition of PIPs, for example, the nature of the acyl chains associated with PI(4,5)P 2 for activation of the GIRK1/GIRK4 potassium channel (13,14), and the importance of saturated fatty acids associated with PIPs to address these lipids in plant lipid rafts (15). In S. cerevisiae, stearic acid accounts for a few p...

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Section: Discussionmentioning

confidence: 99%

Requirement of Phosphoinositides Containing Stearic Acid To Control Cell Polarity

Doignon

Laquel

Testet

et al. 2016

Molecular and Cellular Biology

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“…, 2014; D’Souza and Epand, 2015). Alternatively, PI/PIP acyl chains may be remodeled postsynthesis by the action of phospholipases and acyltransferases (Shindou and Shimizu, 2009; Imae et al. , 2011; Kim et al.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed a similar role has been proposed for the Caenorhabditis elegans homologues of LYCAT (Imae et al. , 2010, 2011). LYCAT may also remodel the acyl chain profile of cardiolipin (CL; Cao et al.…”

Section: Introductionmentioning

confidence: 99%

The acyltransferase LYCAT controls specific phosphoinositides and related membrane traffic

Bone

Dayam

Lee

et al. 2017

MBoC

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Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their functionality. Phosphatidylinositol (PI) and PIPs have a unique enrichment of 1-stearoyl-2-arachidonyl acyl species; however, the regulation and function of this specific acyl profile remains poorly understood. We examined the role of the PI acyltransferase LYCAT in control of PIPs and PIPdependent membrane traffic. LYCAT silencing selectively perturbed the levels and localization of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol-3-phosphate and the membrane traffic dependent on these specific PIPs but was without effect on phosphatidylinositol-4-phosphate or biosynthetic membrane traffic. The acyl profile of PI(4,5)P 2 was selectively altered in LYCAT-deficient cells, whereas LYCAT localized with phosphatidylinositol synthase. We propose that LYCAT remodels the acyl chains of PI, which is then channeled into PI(4,5)P 2 . Our observations suggest that the PIP acyl chain profile may exert broad control of cell physiology. INTRODUCTIONPhosphoinositides (PIPs) control many facets of cell physiology, such as nutrient uptake, receptor signaling, and cell adhesion by control of specific stages of membrane traffic (Di Paolo and De Camilli, 2006;Krauss and Haucke, 2007). Through the action of lipid kinases and phosphatases, PIPs can be interconverted into seven different species defined by phosphorylation of the inositol head group (Balla, 2013). Each of the seven PIPs exhibits unique enrichment within membrane compartments and helps to recruit a variety of cognate effector proteins. Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) and phosphatidylinositol-3-phosphate (PI(3)P) illustrate these concepts well.PI(4,5)P 2 predominates within the plasma membrane (PM) and regulates clathrin-mediated endocytosis (referred to here as endocytosis) to control the internalization of cell surface proteins such as transferrin (Tfn) receptor (TfR;Jost et al., 1998;Varnai et al., 2006;Zoncu et al., 2007;Posor et al., 2013). PI(4,5)P 2 binds to and recruits AP2 and other proteins, which, together with cargo molecules and clathrin, initiate the formation and assembly of clathrin-coated pits (CCPs; Gaidarov and Keen, 1999;Itoh et al., 2001;Jackson et al., 2010). CCPs couple cargo selection to membrane invagination and eventually undergo scission from the PM by the GTPase dynamin2 to yield endocytic vesicles (Conner and Schmid, 2003;McMahon and Boucrot, 2011). CCPs harbor lipid phosphatases such as synaptojanins and OCRL that mediate PI(4,5)P 2 turnover to control the efficiency of vesicle formation (Antonescu et al., 2011) and, afterMonitoring Editor

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“…Hyperthyroidism causes oxidative stress and lipid peroxidation, which has been shown to stimulate the mRNA expression of ALCAT1 in the heart and in isolated cardiomyocytes (6,24). To identify a role of ALCAT1 in the pathogenesis of mitochondrial dysfunction in cardiomyopathy, we next analyzed the effect of hyperthyroidism on the expression of the ALCAT1 protein by Western blot analysis using monoclonal anti-ALCAT1 antibodies recently developed in one of our labs (15). In support of a potential role of ALCAT1 in the etiology of hypertrophic cardiomyopathy, ALCAT1 protein expression in the heart was significantly upregulated by the onset of hyperthyroid cardiomyopathy ( Fig.…”

Section: Alcat1mentioning

confidence: 99%

Ablation of ALCAT1 Mitigates Hypertrophic Cardiomyopathy through Effects on Oxidative Stress and Mitophagy

Liu

Miller

et al. 2012

Molecular and Cellular Biology

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Oxidative stress causes mitochondrial dysfunction and heart failure through unknown mechanisms. Cardiolipin (CL), a mitochondrial membrane phospholipid required for oxidative phosphorylation, plays a pivotal role in cardiac function. The onset of age-related heart diseases is characterized by aberrant CL acyl composition that is highly sensitive to oxidative damage, leading to CL peroxidation and mitochondrial dysfunction. Here we report a key role of ALCAT1, a lysocardiolipin acyltransferase that catalyzes the synthesis of CL with a high peroxidation index, in mitochondrial dysfunction associated with hypertrophic cardiomyopathy. We show that ALCAT1 expression was potently upregulated by the onset of hyperthyroid cardiomyopathy, leading to oxidative stress and mitochondrial dysfunction. Accordingly, overexpression of ALCAT1 in H9c2 cardiac cells caused severe oxidative stress, lipid peroxidation, and mitochondrial DNA (mtDNA) depletion. Conversely, ablation of ALCAT1 prevented the onset of T4-induced cardiomyopathy and cardiac dysfunction. ALCAT1 deficiency also mitigated oxidative stress, insulin resistance, and mitochondrial dysfunction by improving mitochondrial quality control through upregulation of PINK1, a mitochondrial GTPase required for mitochondrial autophagy. Together, these findings implicate a key role of ALCAT1 as the missing link between oxidative stress and mitochondrial dysfunction in the etiology of age-related heart diseases.

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LYCAT, a homologue of C. elegans acl-8,acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice

Cited by 57 publications

References 31 publications

Requirement of Phosphoinositides Containing Stearic Acid To Control Cell Polarity

Requirement of Phosphoinositides Containing Stearic Acid To Control Cell Polarity

The acyltransferase LYCAT controls specific phosphoinositides and related membrane traffic

Ablation of ALCAT1 Mitigates Hypertrophic Cardiomyopathy through Effects on Oxidative Stress and Mitophagy

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