Journal
EMBO JOURNAL
Volume 40, Issue 11, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019104123
Keywords
CHOP; human ENDOU-1; translational control; uORF; Zebrafish Endouc
Categories
Funding
- National Science Council, Taiwan [109-2313-B-715-002, 109-2313-B-715-003]
- Mackay Medical College, Taiwan [1091B12, 1081B12, 1051B19]
- Liver Disease Prevention and Treatment Research Foundation, Taiwan
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
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The study reveals that Endouc/ENDOU-1 can enhance CHOP mRNA translation by cleaving the huORF(chop) transcript to release its inhibitory effect on downstream ORF, leading to increased levels of CHOP protein.
Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2 alpha phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced. We analyzed a 105-nt inhibitory uORF in the transcript of human CHOP (huORF(chop)) and found that overexpression of the zebrafish or human ENDOU poly(U)-endoribonuclease (Endouc or ENDOU-1, respectively) increases CHOP mRNA translation also in the absence of stress. We also found that Endouc/ENDOU-1 binds and cleaves the huORF(chop) transcript at position 80G-81U, which induces CHOP translation independently of phosphorylated eIF2 alpha. However, both ENDOU and phospho-eIF2 alpha are nonetheless required for maximal translation of CHOP mRNA. Increased levels of ENDOU shift a huORF(chop) reporter as well as endogenous CHOP transcripts from the monosome to polysome fraction, indicating an increase in translation. Furthermore, we found that the uncapped truncated huORF(chop)-69-105-nt transcript contains an internal ribosome entry site (IRES), facilitating translation of the cleaved transcript. Therefore, we propose a model where ENDOU-mediated transcript cleavage positively regulates CHOP translation resulting in increased CHOP protein levels upon stress. Specifically, CHOP transcript cleavage changes the configuration of huORF(chop) thereby releasing its inhibition and allowing the stalled ribosomes to resume translation of the downstream ORF.
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