Abstract
The hypoxia‐inducible factor 1a (HIF1a) is a key regulator of stress response and metabolism. Its expression level is known to be controlled by oxygen sensing with two critical proline residues followed by ubiquitination via the pVHL pathway. Here, we report that the degradation of HIF1a is also controlled by N‐terminal arginylation mediated by Arginyltransferase 1 (Ate1) according to the N‐end rule pathway. We found that this mechanism is separate from the classical pVHL‐pathway and it affects cellular Warburg effect, which is the preferred usage of glycolysis that are commonly seen in cancer cells. Furthermore, we found that Ate1, the only arginylation enzyme in animals, appears to have originated from mitochondrial gene transfer. At least a subset of Ate1 is located inside mitochondria and appears to be essential for the composition and functions of respiration complex II. Our study therefore suggest Ate1 as a master regulator of metabolism in cancer cells through arginylation modification of HIF1a.
Support or Funding Information
This study is supported by NIGMS R01 GM 107333, and a start‐up funding from the University of Miami.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.