StAR-related lipid transfer domain 11 (STARD11)-mediated ceramide transport mediates extracellular vesicle biogenesis

被引:39
作者
Fukushima, Masanori [1 ,2 ]
Dasgupta, Debanjali [1 ]
Mauer, Amy S. [1 ]
Kakazu, Eiji [1 ,3 ]
Nakao, Kazuhiko [2 ]
Malhi, Harmeet [1 ]
机构
[1] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA
[2] Nagasaki Univ, Grad Sch Biomed Sci, Dept Gastroenterol & Hepatol, 1-7-1 Sakamoto, Nagasaki 8528501, Japan
[3] Tohoku Univ Hosp, Div Gastroenterol, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan
基金
美国国家卫生研究院;
关键词
extracellular vesicles; exosome (vesicle); ceramide; lipid trafficking; endoplasmic reticulum (ER); endosome; lipotoxicity; lipid metabolism; hepatocyte; palmitate; PROTEIN CERT; MULTIVESICULAR ENDOSOMES; ENDOPLASMIC-RETICULUM; STRUCTURAL BASIS; FFAT MOTIF; TRAFFICKING; EXOSOMES; RELEASE; CELLS; HEPATOCYTES;
D O I
10.1074/jbc.RA118.002587
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Extracellular vesicles are important carriers of cellular materials and have critical roles in cell-to-cell communication in both health and disease. Ceramides are implicated in extracellular vesicle biogenesis, yet the cellular machinery that mediates the formation of ceramide-enriched extracellular vesicles remains unknown. We demonstrate here that the ceramide transport protein StAR-related lipid transfer domain 11 (STARD11) mediates the release of palmitate-stimulated extracellular vesicles having features consistent with exosomes. Using palmitate as a model of lipotoxic diseases and as a substrate for ceramide biosynthesis in human and murine liver cell lines and primary mouse hepatocytes, we found that STARD11-deficient cells release fewer extracellular vesicles. Moreover, STARD11 reciprocally regulated exosome ceramide enrichment and cellular ceramide depletion. We further observed that in STARD11 knockout cells intracellular ceramide accumulates and that this apparent inability to transfer cellular ceramide into extracellular vesicles reduces cellular viability. Using endogenous markers, we uncovered structural and functional colocalization of the endoplasmic reticulum (ER), STARD11, and multivesicular bodies. This colocalization increased following palmitate treatment, suggesting a functional association that may mediate ceramide trafficking from the ER to the multivesicular body. However, the size and number of multivesicular bodies were comparable in WT and STARD11-knockout cells. In conclusion, we propose a model of how STARD11 mediates ceramide trafficking in palmitate-treated cells and stimulates exosome biogenesis.
引用
收藏
页码:15277 / 15289
页数:13
相关论文
共 37 条
[1]   Give lipids a START: The StAR-related lipid transfer (START) domain in mammals [J].
Alpy, F ;
Tomasetto, C .
JOURNAL OF CELL SCIENCE, 2005, 118 (13) :2791-2801
[2]   Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver [J].
Costa-Silva, Bruno ;
Aiello, Nicole M. ;
Ocean, Allyson J. ;
Singh, Swarnima ;
Zhang, Haiying ;
Thakur, Basant Kumar ;
Becker, Annette ;
Hoshino, Ayuko ;
Mark, Milica Tesic ;
Molina, Henrik ;
Xiang, Jenny ;
Zhang, Tuo ;
Theilen, Till-Martin ;
Garcia-Santos, Guillermo ;
Williams, Caitlin ;
Ararso, Yonathan ;
Huang, Yujie ;
Rodrigues, Goncalo ;
Shen, Tang-Long ;
Labori, Knut Jorgen ;
Lothe, Inger Marie Bowitz ;
Kure, Elm H. ;
Hernandez, Jonathan ;
Doussot, Alexandre ;
Ebbesen, Saya H. ;
Grandgenett, Paul M. ;
Hollingsworth, Michael A. ;
Jain, Maneesh ;
Mallya, Kavita ;
Batra, Surinder K. ;
Jarnagin, William R. ;
Schwartz, Robert E. ;
Matei, Irina ;
Peinado, Hector ;
Stanger, Ben Z. ;
Bromberg, Jacqueline ;
Lyden, David .
NATURE CELL BIOLOGY, 2015, 17 (06) :816-+
[3]   Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis [J].
De Almeida, IT ;
Cortez-Pinto, H ;
Fidalgo, G ;
Rodrigues, D ;
Camilo, ME .
CLINICAL NUTRITION, 2002, 21 (03) :219-223
[4]   Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas [J].
Faubion, WA ;
Guicciardi, ME ;
Miyoshi, H ;
Bronk, SF ;
Roberts, PJ ;
Svingen, PA ;
Kaufmann, SH ;
Gores, GJ .
JOURNAL OF CLINICAL INVESTIGATION, 1999, 103 (01) :137-145
[5]   Endoplasmic reticulum-endosome contact increases as endosomes traffic and mature [J].
Friedman, Jonathan R. ;
DiBenedetto, Jared R. ;
West, Matthew ;
Rowland, Ashley A. ;
Voeltz, Gia K. .
MOLECULAR BIOLOGY OF THE CELL, 2013, 24 (07) :1030-1040
[6]   Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2 [J].
Ghossoub, Rania ;
Lembo, Frederique ;
Rubio, Aude ;
Gaillard, Carole Baron ;
Bouchet, Jerome ;
Vitale, Nicolas ;
Slavik, Josef ;
Machala, Miroslav ;
Zimmermann, Pascale .
NATURE COMMUNICATIONS, 2014, 5
[7]   Molecular machinery for non-vesicular trafficking of ceramide [J].
Hanada, K ;
Kumagai, K ;
Yasuda, S ;
Miura, Y ;
Kawano, M ;
Fukasawa, M ;
Nishijima, M .
NATURE, 2003, 426 (6968) :803-809
[8]   Co-evolution of sphingomyelin and the ceramide transport protein CERT [J].
Hanada, Kentaro .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2014, 1841 (05) :704-719
[9]   Extracellular Vesicles in Liver Pathobiology: Small Particles With Big Impact [J].
Hirsova, Petra ;
Ibrahim, Samar H. ;
Verma, Vikas K. ;
Morton, Leslie A. ;
Shah, Vijay H. ;
LaRusso, Nicholas F. ;
Gores, Gregory J. ;
Malhi, Harmeet .
HEPATOLOGY, 2016, 64 (06) :2219-2233
[10]   Structural basis of FFAT motif-mediated ER targeting [J].
Kaiser, SE ;
Brickner, JH ;
Reilein, AR ;
Fenn, TD ;
Walter, P ;
Brunger, AT .
STRUCTURE, 2005, 13 (07) :1035-1045