TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation.

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.

• Authors: Sijia Fan, Jing Wang, Guangqing Yu, Fangjing Rong, Dawei Zhang, Chenxi Xu, Juan Du, Zhi Li, Gang Ouyang, Wuhan Xiao
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 48 Pg. 16299-16313 (11 27 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32963106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Fan et al.

Chemical References

• Tumor Suppressor Proteins
• Vhl protein, zebrafish
• Zebrafish Proteins
• DNA
• TET2 protein, zebrafish
• Dioxygenases
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Amino Acid Motifs
• Animals
• DNA (genetics, metabolism)
• DNA Methylation
• Dioxygenases (genetics, metabolism)
• HEK293 Cells
• Humans
• Hypoxia-Inducible Factor-Proline Dioxygenases (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Zebrafish (genetics, metabolism)
• Zebrafish Proteins (genetics, metabolism)