Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor
| Autor: | Yiguo Zhang, Zhengwen Zhang, Yuancai Xiang, Shaofan Hu, Meng Wang, Josefin Halin, Zhuo Fan, Peter Mattjus, Lu Qiu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Transcriptional Activation Proteasome Endopeptidase Complex Proteolysis NF-E2-Related Factor 1 Toxicology Endoplasmic Reticulum Cell Line 03 medical and health sciences Mice Cytosol Ubiquitin Chlorocebus aethiops medicine Animals Humans Protein Isoforms NRF1 Amino Acid Sequence Transcription factor Pharmacology Cell Nucleus Nucleoplasm medicine.diagnostic_test biology Chemistry Endoplasmic reticulum Sterol regulatory element-binding protein Cell biology 030104 developmental biology HEK293 Cells Proteasome Gene Expression Regulation COS Cells biology.protein Peptides Sequence Alignment Transcription Factors |
| Zdroj: | Toxicology and applied pharmacology. 360 |
| ISSN: | 1096-0333 |
| Popis: | The topobiological behaviour of Nrf1 dictates its post-translational modification and its ability to transactivate target genes. Here, we have elucidated that topovectorial mechanisms control the juxtamembrane processing of Nrf1 on the cyto/nucleoplasmic side of endoplasmic reticulum (ER), whereupon it is cleaved and degraded to remove various lengths of its N-terminal domain (NTD, also refold into a UBL module) and acidic domain-1 (AD1) to yield multiple isoforms. Notably, an N-terminal ∼12.5-kDa polypeptide of Nrf1 arises from selective cleavage at an NHB2-adjoining region within NTD, whilst other longer UBL-containing isoforms may arise from proteolytic processing of the protein within AD1 around PEST1 and Neh2L degrons. The susceptibility of Nrf1 to proteolysis is determined by dynamic repositioning of potential UBL-adjacent degrons and cleavage sites from the ER lumen through p97-driven retrotranslocation and -independent pathways into the cyto/nucleoplasm. These repositioned degrons and cleavage sites within NTD and AD1 of Nrf1 are coming into theirbona fidefunctionality, thereby enabling it to be selectively processed by cytosolic DDI-1/2 proteases and also degradedvia26S proteasomes. The resultant proteolytic processing of Nrf1 gives rise to a mature ∼85-kDa CNC-bZIP transcription factor, which regulates transcriptional expression of cognate target genes. Furthermore, putative ubiquitination of Nrf1 is not a prerequisite necessary for involvement of p97 in the client processing. Overall, the regulated juxtamembrane proteolysis (RJP) of Nrf1, though occurring in close proximity to the ER, is distinctive from the mechanism that regulates the intramembrane proteolytic (RIP) processing of ATF6 and SREBP1. |
| Databáze: | OpenAIRE |
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