CGI-58, the Causative Gene for Chanarin-Dorfman Syndrome, Mediates Acylation of Lysophosphatidic Acid

Ghosh, Ananda K.; Ramakrishnan, Geetha; Chitraju, Chandramohan; Rajasekharan, Ram

doi:10.1074/jbc.m801783200

Cited by 118 publications

(148 citation statements)

References 26 publications

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“…6C, LPAAT activities of all N-terminal deletions and the triple-mutant of CGI-58 were equivalent to wild type. In agreement with published data, no acyltransferase activity was observed using lysophosphatidylcholine as substrate (4,5).…”

Section: Localization Stimulation Capacity and Protein-protein Intesupporting

confidence: 81%

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The N-terminal Region of Comparative Gene Identification-58 (CGI-58) Is Important for Lipid Droplet Binding and Activation of Adipose Triglyceride Lipase

Gruber

Cornaciu

Lass

et al. 2010

Journal of Biological Chemistry

103

135

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In mammals, excess energy is stored in the form of triacylglycerol primarily in lipid droplets of white adipose tissue. The first step of lipolysis (i.e. the mobilization of fat stores) is catalyzed by adipose triglyceride lipase (ATGL). The enzymatic activity of ATGL is strongly enhanced by CGI-58 (comparative gene identification-58), and the loss of either ATGL or CGI-58 function causes systemic triglyceride accumulation in humans and mice. However, the mechanism by which CGI-58 stimulates ATGL activity is unknown. To gain insight into CGI-58 function using structural features of the protein, we generated a threedimensional homology model based on sequence similarity with other proteins. Interestingly, the model of CGI-58 revealed that the N terminus forms an extension of the otherwise compact structure of the protein. This N-terminal region (amino acids 1-30) harbors a lipophilic tryptophan-rich stretch, which affects the localization of the protein.1 H NMR experiments revealed strong interaction between the N-terminal peptide and dodecylphosphocholine micelles as a lipid droplet-mimicking system. A role for this N-terminal region of CGI-58 in lipid droplet binding was further strengthened by localization studies in cultured cells. Although wild-type CGI-58 localizes to the lipid droplet, the N-terminally truncated fragments of CGI-58 are dispersed in the cytoplasm. Moreover, CGI-58 lacking the N-terminal extension loses the ability to stimulate ATGL, implying that the ability of CGI-58 to activate ATGL is linked to correct localization. In summary, our study shows that the N-terminal, Trp-rich region of CGI-58 is essential for correct localization and ATGL-activating function of CGI-58.The protein CGI-58 (comparative gene identification-58; identical to ABHD5 (abhydrolase domain-containing protein 5)) plays an important role in mammalian fatty acid metabolism (1, 2). Interaction of CGI-58 with adipose triglyceride lipase (ATGL), 2 the enzyme catalyzing the first step of lipolysis, enhances the hydrolytic activity of ATGL up to 20-fold (1, 3). CGI-58 is predicted to harbor an ␣/␤-hydrolase domain. Typically, ␣/␤-hydrolases exert their catalytic activity via a catalytic triad. In the case of CGI-58, however, the putative active site serine is replaced by an asparagine residue. Consequently, no triglyceride (TG)-hydrolyzing activity could be detected for the protein.Very recently, lysophosphatidic acid acyltransferase (LPAAT) activity of CGI-58 was discovered and kinetically characterized (4, 5). In humans, mutations in CGI-58 are associated with the development of neutral lipid storage disease with ichthyosis, which is also known as Chanarin Dorfman syndrome. These patients accumulate neutral lipids in various tissues and cell types, including granulocytes, and suffer from non-bullous congenital ichthyosiform erythroderma (2, 6, 7). Mutant forms of CGI-58 detected in patients with neutral lipid storage disease with ichthyosis harboring nonsense or missense mutations (recently reviewed in Ref. 8) are not compet...

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Section: Localization Stimulation Capacity and Protein-protein Intesupporting

confidence: 81%

“…Very recently, lysophosphatidic acid acyltransferase (LPAAT) activity of CGI-58 was discovered and kinetically characterized (4,5). In humans, mutations in CGI-58 are associated with the development of neutral lipid storage disease with ichthyosis, which is also known as Chanarin Dorfman syndrome.…”

mentioning

confidence: 99%

The N-terminal Region of Comparative Gene Identification-58 (CGI-58) Is Important for Lipid Droplet Binding and Activation of Adipose Triglyceride Lipase

Gruber

Cornaciu

Lass

et al. 2010

Journal of Biological Chemistry

103

135

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“…1A)] that is absent from vertebrate (humans, mice, and zebrafish) proteins. Although the plant and yeast CGI-58 proteins appear to possess detectable amounts of TAG lipase and phospholipase A activities in addition to LPAAT activity (19), the human protein does not (17,20). Two Arabidopsis lines with reported T-DNA disruptions in the first exon and intron of the CGI-58 locus (SALK_136871 and SALK_127083, respectively; both sequenced and annotated by the J. Ecker laboratory, Salk Institute, La Jolla, CA) were identified (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1A). Interestingly, the human CGI-58 protein has lysophosphatidic acid acyltransferase (LPAAT) activity but not lipase activity (17,18). In contrast, the plant and yeast proteins possess a canonical lipase sequence motif [-GXSXG-, (Fig.…”

Section: Resultsmentioning

confidence: 99%

Disruption of theArabidopsisCGI-58 homologue produces Chanarin–Dorfman-like lipid droplet accumulation in plants

James

Horn

Case

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

131

124

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CGI-58 is the defective gene in the human neutral lipid storage disease called Chanarin-Dorfman syndrome. This disorder causes intracellular lipid droplets to accumulate in nonadipose tissues, such as skin and blood cells. Here, disruption of the homologous CGI-58 gene in Arabidopsis thaliana resulted in the accumulation of neutral lipid droplets in mature leaves. Mass spectroscopy of isolated lipid droplets from cgi-58 loss-of-function mutants showed they contain triacylglycerols with common leaf-specific fatty acids. Leaves of mature cgi-58 plants exhibited a marked increase in absolute triacylglycerol levels, more than 10-fold higher than in wild-type plants. Lipid levels in the oil-storing seeds of cgi-58 loss-of-function plants were unchanged, and unlike mutations in β-oxidation, the cgi-58 seeds germinated and grew normally, requiring no rescue with sucrose. We conclude that the participation of CGI-58 in neutral lipid homeostasis of nonfat-storing tissues is similar, although not identical, between plant and animal species. This unique insight may have implications for designing a new generation of technologies that enhance the neutral lipid content and composition of crop plants.compartmentation | plant lipid metabolism P lants synthesize and store neutral lipids such as triacylglycerols (TAGs) primarily in cytosolic lipid droplets of maturing seeds (1, 2). In domesticated oilseeds, these stored TAGs represent a major source of calories for human and animal nutrition, an excellent feedstock for diesel fuels, and a reservoir for the deposition of industrially important fatty acids used as chemical feedstocks (3-6). Although not commonly appreciated, TAGs also are synthesized in nonseed tissues (7,8), but their abundance in these tissues is low, in part because of the metabolism of the cell and perhaps as a consequence of the continuous recycling of fatty acids for energy and membrane synthesis. Indeed, vegetative cells can incorporate radiolabeled precursors into TAG (7, 8), they express diacylglycerol acyltransferases [the only enzyme in the "Kennedy pathway" unique to TAG production (9)], and they can accumulate TAGs in β-oxidation mutants (2) and in some floral (10) and fruit (7) tissues. Thus, although plant vegetative cells appear to have the metabolic machinery to synthesize and accumulate neutral lipids, there are likely underlying regulatory mechanisms in place to minimize this process, none of which are understood.Chanarin-Dorfman syndrome is a neutral-lipid storage disease (11) caused by a defect in the protein CGI-58 (comparative gene identification-58, also called ABHD5 for α/β hydrolase-5). CGI-58 is a soluble enzyme that associates with cytosolic lipid droplets under certain metabolic conditions and appears to play a role in hydrolysis of stored lipids (11)(12)(13)(14). Several different mutations in this protein, including amino acid substitutions, premature stop codons, and defects in mRNA splicing, have been identified in various Chanarin-Dorfman patients, all of which result in a hyperac...

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“…[40][41][42] CGI-58 (Comparative Gene Identification-58), an LDS protein with lysophosphatidic acid acyltransferase activity, 43 may serve as colipase for ATGL 44 and is deficient in neutral lipid storage disease (MIM 275630). In different systems, ATGL has been reported to be important for adrenergic lipolysis, 45 basal lipolysis 22 or both.…”

Section: Adipose Triglyceride Lipasementioning

confidence: 99%

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair

Mitchell

2009

Int J Obes

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The current epidemic of childhood obesity will be a serious threat to population health for at least the next several decades. The biology of childhood obesity was the theme of an international symposium held in November 2007. Speakers discussed monogenic causes of obesity, prenatal epigenetic programing, neurobehavioral aspects of obesity, and hormonal and neuroendocrine abnormalities, and the insights provided by non-murine models for understanding the biology of early-onset obesity. Several new developments have been reported in white and brown adipose tissue biology. They are summarized briefly in this review and include observations about cell lineage of adipocytes, the renewal of adipocytes throughout life and the numerous factors that influence adipocyte fatty acid release. The biological underpinnings of childhood obesity are multiple and complex.

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CGI-58, the Causative Gene for Chanarin-Dorfman Syndrome, Mediates Acylation of Lysophosphatidic Acid

Cited by 118 publications

References 26 publications

The N-terminal Region of Comparative Gene Identification-58 (CGI-58) Is Important for Lipid Droplet Binding and Activation of Adipose Triglyceride Lipase

The N-terminal Region of Comparative Gene Identification-58 (CGI-58) Is Important for Lipid Droplet Binding and Activation of Adipose Triglyceride Lipase

Disruption of theArabidopsisCGI-58 homologue produces Chanarin–Dorfman-like lipid droplet accumulation in plants

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair

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