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

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1514-1524
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1864
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • Ceramide
  • Fatty acids
  • Peroxisomes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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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