A zinc finger HIT domain-containing protein, ZNHIT-1, interacts with orphan nuclear hormone receptor Rev-erbbeta and removes Rev-erbbeta-induced inhibition of apoCIII transcription.
The orphan receptors, Rev-erbalpha and Rev-erbbeta, are members of the nuclear receptor superfamily and specifically repress apolipoprotein CIII (apoCIII) gene expression in rats and humans. Moreover, Rev-erbalpha null mutant mice have elevated very low density lipoprotein triacylglycerol and apoCIII levels. However, ligands for Rev-erb are unknown and the regulatory mechanism of Rev-erb is poorly understood. Conceivably, cofactors for Rev-erb may play an important role in the regulation of lipid metabolism. In this study, a zinc finger HIT domain-containing protein, ZNHIT-1, interacted with Rev-erbbeta. ZNHIT-1 was found to be a conserved protein in eukaryotes and was highly abundant in human liver. Furthermore, ZNHIT-1 was identified as a nuclear protein. Serial truncated fragments and substitution mutations established a putative nuclear localization signal at amino acids 38-47 of ZNHIT-1. A putative ligand-binding domain of Rev-erbbeta and the FxxLL motif of ZNHIT-1 were required for their interaction. Finally, ZNHIT-1 was recruited by Rev-erbbeta to the apoCIII promoter and removed the Rev-erbbeta-induced inhibition of apoCIII transcription. These findings demonstrate that ZNHIT-1 functions as a cofactor to regulate the activity of Rev-erbbeta, and may play a role in lipid metabolism.
Wang
Jiadong
J
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
Li
Yang
Y
Zhang
Min
M
Liu
Zhongle
Z
Wu
Cong
C
Yuan
Hanying
H
Li
Yu-Yang
YY
Zhao
Xin
X
Lu
Hong
H
D000595:Amino Acid Sequence; D053305:Apolipoprotein C-III / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015723:Gene Library; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D016335:Zinc Fingers
D053305:Apolipoprotein C-III; D004268:DNA-Binding Proteins; C090977:NR1D2 protein, human; D019913:Nuclear Localization Signals; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; C524753:ZNHIT1 protein, human; D008156:Luciferases; D005982:Glutathione Transferase