Structural Basis for the Golgi Association by the Pleckstrin Homology Domain of the Ceramide Trafficking Protein (CERT)

Sugiki, Toshihiko; Takeuchi, Koh; Yamaji, Taiki; Takano, Toshiaki; Tokunaga, Yuji; Kumagai, Keigo; Hanada, Kentaro; Takahashi, Hideo; Shimada, Ichio

doi:10.1074/jbc.m112.367730

Cited by 57 publications

(96 citation statements)

References 57 publications

(79 reference statements)

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“…The interaction between PtdIns(4)P and the PH domain of CERT is indispensable for the transport of ceramide from ER to Golgi [50]. Therefore, CERT-transported ceramide may colocalize with PtdIns(4)P, thereby inhibiting, or interrupting, transfer of glucose from UDPglucose to ceramide by UGCG (Fig.…”

Section: Ceramide Transport Protein (Cert) and Glccer Synthesismentioning

confidence: 95%

New insights on glucosylated lipids: Metabolism and functions

Ishibashi

Kohyama-Koganeya

Hirabayashi

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

124

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Ceramide, cholesterol, and phosphatidic acid are major basic structures for cell membrane lipids. These lipids are modified with glucose to generate glucosylceramide (GlcCer), cholesterylglucoside (ChlGlc), and phosphatidylglucoside (PtdGlc), respectively. Glucosylation dramatically changes the functional properties of lipids. For instance, ceramide acts as a strong tumor suppressor that causes apoptosis and cell cycle arrest, while GlcCer has an opposite effect, downregulating ceramide activities. All glucosylated lipids are enriched in lipid rafts or microdomains and play fundamental roles in a variety of cellular processes. In this review, we discuss the biological functions and metabolism of these three glucosylated lipids.

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Section: Ceramide Transport Protein (Cert) and Glccer Synthesismentioning

confidence: 95%

New insights on glucosylated lipids: Metabolism and functions

Ishibashi

Kohyama-Koganeya

Hirabayashi

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

124

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“…11). OSBP at membrane contact sites would increase the local concentration of PI-4P (and perhaps Arf1), generating a membrane platform for recruitment of other transport proteins with structur- ally related PH domains that recognize PI-4P, such as CERT (39). Recruitment of CERT would increase ceramide transport to the Golgi apparatus for SM synthesis (21, 23).…”

Section: Discussionmentioning

confidence: 99%

Oxysterol-binding Protein Activation at Endoplasmic Reticulum-Golgi Contact Sites Reorganizes Phosphatidylinositol 4-Phosphate Pools

Goto

Charman

Ridgway

2016

Journal of Biological Chemistry

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Oxysterol-binding protein (OSBP) exchanges cholesterol and phosphatidylinositol 4-phosphate (PI-4P) at contact sites between the endoplasmic reticulum (ER) and the trans-Golgi/ trans-Golgi network. 25-Hydroxycholesterol (25OH) competitively inhibits this exchange reaction in vitro and causes the constitutive localization of OSBP at the ER/Golgi interface and PI-4P-dependent recruitment of ceramide transfer protein (CERT) for sphingomyelin synthesis. We used PI-4P probes and mass analysis to determine how OSBP controls the availability of PI-4P for this metabolic pathway. Treatment of fibroblasts or Chinese hamster ovary (CHO) cells with 25OH caused a 50 -70% reduction in Golgi-associated immunoreactive PI-4P that correlated with Golgi localization of OSBP. In contrast, 25OH caused an OSBP-dependent enrichment in Golgi PI-4P that was detected with a pleckstrin homology domain probe. The cellular mass of phosphatidylinositol monophosphates and Golgi PI-4P measured with an unbiased PI-4P probe (P4M) was unaffected by 25OH and OSBP silencing, indicating that OSBP shifts the distribution of PI-4P upon localization to ER-Golgi contact sites. The PI-4P and sterol binding activities of OSBP were both required for 25OH activation of sphingomyelin synthesis, suggesting that 25OH must be exchanged for PI-4P to be concentrated at contact sites. We propose a model wherein 25OH activation of OSBP promotes the binding and retention of PI-4P at ER-Golgi contact sites. This pool of PI-4P specifically recruits pleckstrin homology domain-containing proteins involved in lipid transfer and metabolism, such as CERT.

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“…Lactosylceramide was from Nagara Science (Gifu, Japan). Ricinus communis lectin (RCA 120) was from Vector Laboratories Inc. N-[palmitoyl- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]Palmitoyl-Derythro-sphingosine ([ 14 C]ceramide) (55 mCi/mmol) was from American Radiolabeled Chemicals. ISP-1/myriocin (16) was a gift from Dr. Tetsuro Fujita (Research Institute for Production Development, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…CERT has several functional domains and motifs (Fig. 1A) as follows: (i) a pleckstrin homology (PH) domain capable of binding phosphatidylinositol 4-monophosphate (PtdIns(4)P) for Golgi targeting (9,10); (ii) a steroidogenic acute regulatory protein-related (START) domain, which catalyzes the intermembrane transfer of ceramide (9,11,12); (iii) a short peptidic motif named "two phenylalanines in an acidic tract (FFAT)," capable of associating with VAMP-associated protein (VAP), an ER-resident membrane protein (13); and (iv) a serine-repeat motif (SRM), the phosphorylation of which represses the functions of both the PH and START domains (14). The role of CERT is supposed to rapidly transfer ceramide at the ER-toGolgi membrane contact sites (9,15).…”

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confidence: 99%

Phosphoregulation of the Ceramide Transport Protein CERT at Serine 315 in the Interaction with VAMP-associated Protein (VAP) for Inter-organelle Trafficking of Ceramide in Mammalian Cells

Kumagai

Kawano‐Kawada²,

Hanada

2014

Journal of Biological Chemistry

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Background: CERT transports ceramide from the ER to the Golgi apparatus and is supported by its FFAT motif-dependent binding to the ER membrane protein VAP. Results: CERT is phosphorylated at Ser-315 near the FFAT motif. Conclusion:The phosphorylation strengthens the CERT-VAP-A interaction to up-regulate ceramide trafficking. Significance: This provides new insights into molecular mechanisms underlying functional regulation of FFAT-containing proteins for the inter-organelle lipid trafficking.

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Structural Basis for the Golgi Association by the Pleckstrin Homology Domain of the Ceramide Trafficking Protein (CERT)

Cited by 57 publications

References 57 publications

New insights on glucosylated lipids: Metabolism and functions

New insights on glucosylated lipids: Metabolism and functions

Oxysterol-binding Protein Activation at Endoplasmic Reticulum-Golgi Contact Sites Reorganizes Phosphatidylinositol 4-Phosphate Pools

Phosphoregulation of the Ceramide Transport Protein CERT at Serine 315 in the Interaction with VAMP-associated Protein (VAP) for Inter-organelle Trafficking of Ceramide in Mammalian Cells

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