Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes

Zhihui Zhu; Jianzhong Chen; Guanghu Wang; Ahmed Elsherbini; Liansheng Zhong; Xue Jiang; Haiyan Qin; Priyanka Tripathi; Wenbo Zhi; Stefka D. Spassieva; Andrew J. Morris; Erhard Bieberich

doi:10.1016/j.bbalip.2019.05.017

Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes

Zhihui Zhu
, Jianzhong Chen
, Guanghu Wang
, Ahmed Elsherbini
, Liansheng Zhong
, Xue Jiang
, Haiyan Qin
, Priyanka Tripathi
, Wenbo Zhi
, Stefka D. Spassieva
, Andrew J. Morris
, Erhard Bieberich

Producción científica: Article › revisión exhaustiva

13 Citas (Scopus)

Resumen

The sphingolipid ceramide regulates beta-oxidation of medium and long chain fatty acids in mitochondria. It is not known whether it also regulates oxidation of very long chain fatty acids (VLCFAs) in peroxisomes. Using affinity chromatography, co-immunoprecipitation, and proximity ligation assays we discovered that ceramide interacts with Hsd17b4, an enzyme critical for peroxisomal VLCFA oxidation and docosahexaenoic acid (DHA) generation. Immunocytochemistry showed that Hsd17b4 is distributed to ceramide-enriched mitochondria-associated membranes (CEMAMs). Molecular docking and in vitro mutagenesis experiments showed that ceramide binds to the sterol carrier protein 2-like domain in Hsd17b4 adjacent to peroxisome targeting signal 1 (PTS1), the C-terminal signal for interaction with peroxisomal biogenesis factor 5 (Pex5), a peroxin mediating transport of Hsd17b4 into peroxisomes. Inhibition of ceramide biosynthesis induced translocation of Hsd17b4 from CEMAMs to peroxisomes, interaction of Hsd17b4 with Pex5, and upregulation of DHA. This data indicates a novel role of ceramide as a molecular switch regulating interaction of Hsd17b4 with Pex5 and peroxisomal function.

Idioma original	English
Páginas (desde-hasta)	1514-1524
Número de páginas	11
Publicación	Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volumen	1864
N.º	10
DOI	https://doi.org/10.1016/j.bbalip.2019.05.017
Estado	Published - oct 2019

Nota bibliográfica

Publisher Copyright:
© 2019 Elsevier B.V.

Financiación

This work was the supported by the grants R01AG034389, R01NS095215, and NSF 1615874 to EB and a VA Merit Award I01CX001550 and P30 GM127211 to AJM. The authors thank the Department of Physiology (Chair Dr. Alan Daugherty). College of Medicine, University of Kentucky, Lexington, KY for institutional support. This work was the supported by the grants R01AG034389 , R01NS095215 , and NSF 1615874 to EB and a VA Merit Award I01CX001550 and P30 GM127211 to AJM. The authors thank the Department of Physiology (Chair Dr. Alan Daugherty). College of Medicine , University of Kentucky , Lexington , KY for institutional support.

Financiadores	Número del financiador
National Science Foundation Arctic Social Science Program	I01CX001550, P30 GM127211, 1615874
National Science Foundation Arctic Social Science Program
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS095215
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
National Sleep Foundation	R01AG034389
National Sleep Foundation
University of Kentucky

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.bbalip.2019.05.017

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Zhu, Z., Chen, J., Wang, G., Elsherbini, A., Zhong, L., Jiang, X., Qin, H., Tripathi, P., Zhi, W., Spassieva, S. D., Morris, A. J., & Bieberich, E. (2019). Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1864(10), 1514-1524. https://doi.org/10.1016/j.bbalip.2019.05.017

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abstract = "The sphingolipid ceramide regulates beta-oxidation of medium and long chain fatty acids in mitochondria. It is not known whether it also regulates oxidation of very long chain fatty acids (VLCFAs) in peroxisomes. Using affinity chromatography, co-immunoprecipitation, and proximity ligation assays we discovered that ceramide interacts with Hsd17b4, an enzyme critical for peroxisomal VLCFA oxidation and docosahexaenoic acid (DHA) generation. Immunocytochemistry showed that Hsd17b4 is distributed to ceramide-enriched mitochondria-associated membranes (CEMAMs). Molecular docking and in vitro mutagenesis experiments showed that ceramide binds to the sterol carrier protein 2-like domain in Hsd17b4 adjacent to peroxisome targeting signal 1 (PTS1), the C-terminal signal for interaction with peroxisomal biogenesis factor 5 (Pex5), a peroxin mediating transport of Hsd17b4 into peroxisomes. Inhibition of ceramide biosynthesis induced translocation of Hsd17b4 from CEMAMs to peroxisomes, interaction of Hsd17b4 with Pex5, and upregulation of DHA. This data indicates a novel role of ceramide as a molecular switch regulating interaction of Hsd17b4 with Pex5 and peroxisomal function.",

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author = "Zhihui Zhu and Jianzhong Chen and Guanghu Wang and Ahmed Elsherbini and Liansheng Zhong and Xue Jiang and Haiyan Qin and Priyanka Tripathi and Wenbo Zhi and Spassieva, \{Stefka D.\} and Morris, \{Andrew J.\} and Erhard Bieberich",

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AU - Zhu, Zhihui

AU - Chen, Jianzhong

AU - Wang, Guanghu

AU - Elsherbini, Ahmed

AU - Zhong, Liansheng

AU - Jiang, Xue

AU - Qin, Haiyan

AU - Tripathi, Priyanka

AU - Zhi, Wenbo

AU - Spassieva, Stefka D.

AU - Morris, Andrew J.

AU - Bieberich, Erhard

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AB - The sphingolipid ceramide regulates beta-oxidation of medium and long chain fatty acids in mitochondria. It is not known whether it also regulates oxidation of very long chain fatty acids (VLCFAs) in peroxisomes. Using affinity chromatography, co-immunoprecipitation, and proximity ligation assays we discovered that ceramide interacts with Hsd17b4, an enzyme critical for peroxisomal VLCFA oxidation and docosahexaenoic acid (DHA) generation. Immunocytochemistry showed that Hsd17b4 is distributed to ceramide-enriched mitochondria-associated membranes (CEMAMs). Molecular docking and in vitro mutagenesis experiments showed that ceramide binds to the sterol carrier protein 2-like domain in Hsd17b4 adjacent to peroxisome targeting signal 1 (PTS1), the C-terminal signal for interaction with peroxisomal biogenesis factor 5 (Pex5), a peroxin mediating transport of Hsd17b4 into peroxisomes. Inhibition of ceramide biosynthesis induced translocation of Hsd17b4 from CEMAMs to peroxisomes, interaction of Hsd17b4 with Pex5, and upregulation of DHA. This data indicates a novel role of ceramide as a molecular switch regulating interaction of Hsd17b4 with Pex5 and peroxisomal function.

KW - Ceramide

KW - Fatty acids

KW - Peroxisomes

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JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

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IS - 10

ER -

Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes

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ASJC Scopus subject areas

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