3 years ago

Negative regulation of the Keap1-Nrf2 pathway by a p62/Sqstm1 splicing variant.

Yoshinobu Ichimura, Miki Obata, Shun Kageyama, Masaaki Komatsu, Tetsuya Saito, Ryo-Hei Koide
A key anti-oxidant pathway, the Keap1-Nrf2 system, is regulated by p62/Sqstm1 via multiple mechanisms, including gene expression, post-translational modifications such as ubiquitination and phosphorylation, and autophagic degradation of p62/Sqstm1 and Keap1. Herein, we demonstrate a novel mode of regulation of the Keap1-Nrf2 system, mediated by a splicing variant of p62/Sqstm1 pre-mRNA. Ensembl database search and subsequent biochemical analyses in mice revealed the presence of an mRNA that encodes p62/Sqstm1 protein lacking the Keap1-interacting region (KIR), which is essential for the interaction with Keap1. Like full-length p62, the variant was induced under conditions in which Nrf2 was activated (e.g., impairment of autophagy), oligomerized with itself and/or full-length protein, and was degraded by autophagy. However, the variant failed to interact with Keap1 and sequester it into variant-positive aggregates. Remarkably, while full-length p62 stabilized Nrf2 and induced the gene expression of Nrf2 targets, the variant increased the amount of Keap1 and enhanced ubiquitination of Nrf2, thereby suppressing the induction of Nrf2 targets. Hepatocytes isolated from genetically modified mice that express full-length p62, but not the variant, were susceptible to activation of Nrf2 in response to stress. Collectively, our results suggest that splicing of p62/Sqstm1 pre-mRNA negatively regulates the Keap1-Nrf2 pathway.

Publisher URL: http://doi.org/10.1128/MCB.00642-17

DOI: 10.1128/MCB.00642-17

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