Role of hepatic Annexin A6 in fatty acid-induced lipid droplet formation

Cairns, Rose; Álvarez-Guaita, Anna; Martínez-Saludes, Inés; Wason, Sundeep J; Hanh, Jacky; Nagarajan, Shilpa R.; Hosseini‐Beheshti, Elham; Monastyrskaya, Katia; Hoy, Andrew J.; Buechler, Christa; Enrich, Carlos; Rentero, Carles; Grewal, Thomas

doi:10.1016/j.yexcr.2017.07.015

Cited by 18 publications

(31 citation statements)

References 56 publications

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“…In agreement with this, we identified several cancer‐related over‐expressed genes, including Cscbp2 , Apoa4 , Anxa2 , Serpine1 , Igfbp1 , and Tubb2a , that were associated with chromatin‐accessible regions in NASH‐derived HCC. It has been reported that up‐regulation of these genes may have significance in the hepatocarcinogenic process, in general, and in the pathogenesis of NAFLD and NAFLD‐associated liver carcinogenesis, in particular …”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that up-regulation of these genes may have significance in the hepatocarcinogenic process, in general, [39][40][41][42][43][44] and in the pathogenesis of NAFLD and NAFLD-associated liver carcinogenesis, in particular. [45][46][47][48][49] Apoa4 is a critical gene involved in the regulation of multiple metabolic pathways, including lipid absorption, lipid metabolism, and glucose homeostasis. 47 protein was increased in the genetically obese (ob/ob) mice.…”

Section: Discussionmentioning

confidence: 99%

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Identification of chromatin‐accessible domains in non‐alcoholic steatohepatitis‐derived hepatocellular carcinoma

Dechassa

Tryndyak

Conti

et al. 2018

Molecular Carcinogenesis

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Non-alcoholic steatohepatitis (NASH) is becoming one of the major causes of hepatocellular carcinoma (HCC) in the United States and Western countries; however, the molecular mechanisms associated with NASH-related liver carcinogenesis are not well understood. In the present study, we investigated cancer-associated chromatin alterations using a model that resembles the development of NASH-related HCC in humans. An assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) identified 1677 tumor-specific chromatin-accessible regions in NASH-derived HCC tissue samples. Using a combined analysis of ATAC-seq and global gene expression data, we identified 199 differentially expressed genes, 139 up-regulated and 60 down-regulated. Interestingly, 15 of the 139 up-regulated genes had accessible chromatin sites within 5 Kb of the transcription start site (TSS), including Apoa4, Anxa2, Serpine1, Igfbp1, and Tubb2a, genes critically involved in the development of NASH and HCC. We demonstrate that the mechanism for the up-regulation of these genes is associated with the enrichment of chromatin-accessible regions by transcription factors, especially NFATC2, and histone H3K4me1 and H3K27ac gene transcription-activating marks. These data underline the important role of chromatin accessibility perturbations in reshaping of the chromatin landscape in NASH-related HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of chromatin‐accessible domains in non‐alcoholic steatohepatitis‐derived hepatocellular carcinoma

Dechassa

Tryndyak

Conti

et al. 2018

Molecular Carcinogenesis

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“…13), suggesting that VP8 caused an abnormal lipid metabolism in cells. In general, LDs can be found in the cytoplasm (39) and the nucleus (40,41), serving as lipid storage and being involved in cellular lipid metabolism (42). Accordingly, the extra lipid produced in VP8-transfected cells might be stored as nuclear LDs.…”

Section: Fig 4 Legend (Continued)mentioning

confidence: 99%

US3 Kinase-Mediated Phosphorylation of Tegument Protein VP8 Plays a Critical Role in the Cellular Localization of VP8 and Its Effect on the Lipid Metabolism of Bovine Herpesvirus 1-Infected Cells

Donovan

Sucharita

Brownlie

et al. 2019

J Virol

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Bovine herpesvirus 1 (BoHV-1) infects bovine species, causing respiratory infections, genital disorders and abortions. VP8 is the most abundant tegument protein of BoHV-1 and is critical for virus replication in cattle. In this study, the cellular transport of VP8 in BoHV-1-infected cells and its ability to alter the cellular lipid metabolism were investigated. A viral kinase, US3, was found to be involved in regulating these processes. In the early stages of infection VP8 was localized in the nucleus. Subsequently, presumably after completion of its role in the nucleus, VP8 was translocated to the cytoplasm. When US3 was deleted or the essential US3 phosphorylation site of VP8 was mutated in BoHV-1, the majority of VP8 was localized in the nuclei of infected cells. This suggests that phosphorylation by US3 may be critical for cytoplasmic localization of VP8. Eventually, the cytoplasmic VP8 was accumulated in the cis-Golgi apparatus but not in the trans-Golgi network, implying that VP8 was not involved in virion transport toward and budding from the cell membrane. VP8 caused lipid droplet (LD) formation in the nuclei of transfected cells and increased cellular cholesterol levels. Lipid droplets were not found in the nuclei of BoHV-1-infected cells when VP8 was cytoplasmic in the presence of US3. However, when US3 was deleted or phosphorylation residues in VP8 were mutated, nuclear VP8 and LDs appeared in BoHV-1-infected cells. The total cholesterol level was increased in BoHV-1-infected cells but not in ΔU L 47-BoHV-1-infected cells, further supporting a role for VP8 in altering the cellular lipid metabolism during infection. IMPORTANCE Nuclear localization signals (NLSs) and nuclear export signals (NESs) are important elements directing VP8 to the desired locations in the BoHV-1-infected cell. In this study, a critical regulator that switches the nuclear and cytoplasmic localization of VP8 in BoHV-1-infected cells was identified. BoHV-1 used viral kinase US3 to regulate the cellular localization of VP8. Early during BoHV-1 infection VP8 was localized in the nucleus, where it performs various functions; once US3 was expressed, phosphorylated VP8 was cytoplasmic and ultimately accumulated in the cis-Golgi apparatus, presumably to be incorporated into virions. The Golgi localization of VP8 was only observed in virus-infected cells and not in US3-cotransfected cells, suggesting that this is mediated by other viral factors. Interestingly, VP8 was shown to cause increased cholesterol levels, which is a novel function for VP8 and a potential strategy to supply lipid for viral replication. KEYWORDS US3, VP8, bovine herpesvirus 1, cellular localization, lipid metabolism, protein phosphorylation Citation Zhang K, Donovan T, Sucharita S, Brownlie R, Snider M, Tikoo SK, van Drunen Littel-van den Hurk S. 2019. US3 kinasemediated phosphorylation of tegument protein VP8 plays a critical role in the cellular localization of VP8 and its effect on the lipid metabolism of bovine herpesvirus 1-infected cells. J RESULTSNuclear VP8 i...

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“…Annexin A6, as a cholesterol binding and multifunctional scaffold protein plays a crucial role in cell motility [Hayes et al 2004;Monastyrskaya et al 2009;Grewal et al 2017] and is implicated also in cell signaling [Koese et al 2013;Hoque et al 2014;Qi et al 2015;Cornely et al 2016;Raouf et al 2018]. Moreover, annexin A6 has been reported to regulate a formation of multifunctional signaling complexes at the membranes, affect membrane lateral organization, or influence cholesterol metabolism and dis-tribution, but also to participate in the vesicular transport both in endo-and exocytosis [Cubells et al 2007;Garcia-Melero et al 2016;Cairns et al 2017]. In addition, it has been shown that AnxA6 recruited to the plasma membrane is able to affect membrane remodelling, e.g.…”

Section: Mebrane Lateral Organizationmentioning

confidence: 99%

Annexin A6 as a cholesterol and nucleotide binding protein involved in membrane repair and in controlling membrane transport during endo- and exocytosis

Bandorowicz‐Pikuła¹,

Seliga

2018

Postepy Biochem

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Aneksyny, rodzina białek wiążących jony wapnia i błony biologiczne, były badane w Instytucie Biologii Doświadczalnej im. Marcelego Nenckiego w Warszawie od wczesnych lat 90. XX wieku. Szczególną uwagę poświęcono strukturze aneksyn, potencjalnym ligandom tych białek oraz ich funkcji, np. w procesie biomineralizacji zachodzącym w normie i w stanach patologicznych. Wyniki badań prowadzonych w wielu laboratoriach na świecie wskazują, że aneksyny odgrywają bardzo ważną rolę w organizacji błon biologicznych. W tym artykule przeglądowym opisujemy jednego z największych pod względem masy cząsteczkowej przedstawiciela rodziny aneksyn, aneksynę A6 (AnxA6), białko wykazujące zdolność wiązania się z cholesterolem i nukleotydami oraz zmieniające przepuszczalność błony dla jonów w odpowiedzi na obniżenie wewnątrzkomórkowego pH. Dodatkowo, opisano funkcje AnxA6, takie jak udział w tworzeniu mikrodomen błonowych, w naprawie uszkodzeń błony plazmatycznej oraz w regulacji transportu pęcherzykowego.

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Role of hepatic Annexin A6 in fatty acid-induced lipid droplet formation

Cited by 18 publications

References 56 publications

Identification of chromatin‐accessible domains in non‐alcoholic steatohepatitis‐derived hepatocellular carcinoma

Identification of chromatin‐accessible domains in non‐alcoholic steatohepatitis‐derived hepatocellular carcinoma

US3 Kinase-Mediated Phosphorylation of Tegument Protein VP8 Plays a Critical Role in the Cellular Localization of VP8 and Its Effect on the Lipid Metabolism of Bovine Herpesvirus 1-Infected Cells

Annexin A6 as a cholesterol and nucleotide binding protein involved in membrane repair and in controlling membrane transport during endo- and exocytosis

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