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Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma [Quantseq]

GSE254277 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2024/10/22 Platform GPL19057
Summary
Hepatocellular carcinoma (HCC) emerges from chronic inflammation to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that while p62 positively regulates STING ubiquitination by TRIM32 by displacing NBR1, which results in the activation of the interferon (IFN) cascade, NBR1 prevents TRIM32 interaction with and the activation of STING, leading to impaired IFN synthesis. NBR1 also antagonizes STING function by promoting its trafficking from the Golgi to the endosome-lysosomal degradative cascade independent of autophagy. Importantly, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs. The upregulation of the STING-IFN pathway by NBR1 deficiency enhances the anti-tumor response mediated by CD8+ T cells. These results identify NBR1 as a synthetic vulnerability of p62-deficiency in HSCs. NBR1 loss, by promoting the STING/IFN pathway, boosts anti-tumor CD8+ T cell responses to restrain HCC.
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Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma
Nishimura S, Linares JF, L'Hermitte A et al. · Molecular cell 2024 · PMID 39423823 · doi:10.1016/j.molcel.2024.09.026
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Also filed as BioProject PRJNA1069377 and SRA study SRP486066. Searching any of these in the dataset finder brings you back here.

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