TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation
Authors: Zhi Li
Fangjing Rong
Jing Wang
Guangqing Yu
Juan Du
Gang Ouyang
Chenxi Xu
Wuhan Xiao
Sijia Fan
Dawei Zhang
Journal: Journal of Biological Chemistry (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: DNA demethylation; E3 ubiquitin ligase; PHD2; PHD3; TET1
Affiliations: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China., State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China; Innovation Academy of Seed Design, Chinese Academy of Sciences, Wuhan, China., State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China., State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China; Innovation Academy of Seed Design, Chinese Academy of Sciences, Wuhan, China., State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China; Innovation Academy of Seed Design, Chinese Academy of Sciences, Wuhan, China. Electronic address: .

Abstract:  Hypoxia-inducible factors are heterodimeric transcription factors that play a crucial role in a cell's ability to adapt to low oxygen. The von Hippel-Lindau tumor suppressor (pVHL) acts as a master regulator of HIF activity, and its targeting of prolyl hydroxylated HIF-α for proteasomal degradation under normoxia is thought to be a major mechanism for pVHL tumor suppression and cellular response to oxygen. Whether pVHL regulates other targets through a similar mechanism is largely unknown. Here, we identify TET2/3 as novel targets of pVHL. pVHL induces proteasomal degradation of TET2/3, resulting in reduced global 5-hydroxymethylcytosine levels. Conserved proline residues within the LAP/LAP-like motifs of these two proteins are hydroxylated by the prolyl hydroxylase enzymes (PHD2/EGLN1 and PHD3/EGLN3), which is prerequisite for pVHL-mediated degradation. Using zebrafish as a model, we determined that global 5-hydroxymethylcytosine levels are enhanced in vhl-null, egln1a/b-double-null, and egln3-null embryos. Therefore, we reveal a novel function for the PHD-pVHL pathway in regulating TET protein stability and activity. These data extend our understanding of how TET proteins are regulated and provide new insight into the mechanisms of pVHL in tumor suppression. 

Retracted: No

PubPeer comments:
 ![file] Is these duplicated blotsuff1f , 
 Yes, we think that these are duplicated blots. It was caused by wrong operation when we did u201ccopy and pasteu201d to make this figure because of their similar appearance. We have found the original u03b2-actin blot of Figure 6SA and replaced the wrong u03b2-actin blot in the revised figure attached. We will contact the journal office to make a correction. ![file] , 
 #2 Could the authors please provide the original uncropped scans? You may post those here or use a link to an external site (such as Imgur.com or Google Drive) for larger files. ,