TY - JOUR
T1 - Ceramide regulates interaction of Hsd17b4 with Pex5 and function of peroxisomes
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
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
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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U2 - 10.1016/j.bbalip.2019.05.017
DO - 10.1016/j.bbalip.2019.05.017
M3 - Article
C2 - 31176039
AN - SCOPUS:85068078620
SN - 1388-1981
VL - 1864
SP - 1514
EP - 1524
JO - BBA - Specialised Section On Lipids and Related Subjects
JF - BBA - Specialised Section On Lipids and Related Subjects
IS - 10
ER -