2. Academic Validation
  3. UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage

UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage

  • Biochim Biophys Acta Gene Regul Mech. 2023 Apr 19;194937. doi: 10.1016/j.bbagrm.2023.194937.
Xianyan Hu 1,  Rong Zou 1,  Zaihui Zhang 2,  Jia Ji 1,  Jiqiang Li 1,  Xin-Yu Huo 1,  Di Liu 1,  Man-Xi Ge 1,  Meng-Ke Cui 1,  Ming-Zhi Wu 1,  Zhao-Peng Li 1,  Qingchen Wang 3,  Xiaoli Zhang 3,  Zai-Rong Zhang 4
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Pudong New District, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China.
  • 2 Department of Endocrinology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, 2 Hengbu Street, Westlake District, Hangzhou 310000, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Pudong New District, Shanghai 201210, China.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Pudong New District, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China. Electronic address: zrzhang@sioc.ac.cn.
PMID: 37084817 DOI: 10.1016/j.bbagrm.2023.194937
Abstract

The transcription factor nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) regulates constitutive and inducible expression of Proteasome subunits and assembly chaperones. The precursor of NRF1 is integrated into the endoplasmic reticulum (ER) and can be retrotranslocated from the ER to the cytosol where it is processed by ubiquitin-directed endoprotease DDI2. DDI2 cleaves and activates NRF1 only when NRF1 is highly polyubiquitinated. It remains unclear how retrotranslocated NRF1 is primed with very long polyubiquitin chain for subsequent processing. Here, we report that E3 ligase UBE4A catalyzes ubiquitination of retrotranslocated NRF1 and promotes its cleavage. Depletion of UBE4A shortens the average length of polyubiquitin chain of NRF1, decreases NRF1 cleavage efficiency and causes accumulation of non-cleaved, inactivated NRF1. Expression of a UBE4A mutant lacking ligase activity impairs the cleavage, likely due to a dominant negative effect. UBE4A interacts with NRF1 and the recombinant UBE4A can promote ubiquitination of retrotranslocated NRF1 in vitro. In addition, knocking out UBE4A reduces transcription of proteasomal subunits in cells. Our results indicate that UBE4A primes NRF1 for DDI2-mediated activation to facilitate expression of proteasomal genes.

Keywords

DDI2; ERAD; NRF1; Retrotranslocation; UBE4A; Ubiquitination.

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