Research
| Title： | Tet1 facilitates hypoxia tolerance by stabilizing the HIF-alpha proteins independent of its methylcytosine dioxygenase activity |
|---|---|
| First author： | Wang, Jing; Zhang, Dawei; Du, Juan; Zhou, Chi; Li, Zhi; Liu, Xing; Ouyang, Gang; Xiao, Wuhan |
| Journal： | NUCLEIC ACIDS RESEARCH |
| Years： | 2017 |
| DOI： | 10.1093/nar/gkx869 |
| Abstract： | Because of the requirement of oxygen (O-2) to produce energy, aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen in both acute status and chronic status. To date, how organisms tolerate acute hypoxia and the underlying mechanisms remain largely unknown. Here, we identify that Tet1, one member of the ten-eleven translocation (TET) family of methylcytosine dioxygenases, is required for hypoxia tolerance in zebrafish and mice. Tet1-null zebrafish and mice are more sensitive to hypoxic conditions compared with their wild-type siblings. We demonstrate that Tet1 stabilizes hypoxia-inducible factor alpha (HIF-alpha) and enhances HIF-alpha transcription activity independent of its enzymatic activity. In addition, we show that Tet1 modulates HIF-2 alpha and HIF-1 alpha through different mechanisms. Tet1 competes with prolyl hydroxylase protein 2 (PHD2) to bind to HIF-2 alpha, resulting in a reduction of HIF-2 alpha hydroxylation by PHD2. For HIF1 alpha, however, Tet1 has no effect on HIF-1 alpha hydroxylation, but rather it appears to stabilize the C-terminus of HIF-1 alpha by affecting lysine site modification. Furthermore, we found that Tet1 enhances rather than prevents poly-ubiquitination on HIF-alpha. Our results reveal a previously unrecognized function of Tet1 independent of its methylcytosine dioxygenase activity in hypoxia signaling. |
