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RSK1 reprograms the ubiquitin pathway to promote immune suppression

ABSTRACT: Although immune checkpoint blockade (ICB) is an effective therapeutic strategy, tumor intrinsic resistance to ICB limits its benefits for a majority of cancer patients. Via multiple in vivo screens, we identified RNF19A as an immune-suppressor. RNF19A suppresses ICB efficacy by ubiquitinating cGAS to inhibit the release of type I interferon. Surprisingly, UBE2L6, originally identified as a critical interferon-induced ISG15-conjugating E2 enzyme for ISGylation, functions as the major ubiquitin-conjugating E2 enzyme to enable RNF19A-driven cGAS ubiquitination. Further, RSK1 phosphorylates UBE2L6 to switch its substrate from ISG15 to ubiquitin, thus converting it from an immune response enhancer to a suppressor. In xenograft models, targeting RSK1 or blocking UBE2L6 phosphorylation improves immune response. In patient tissues, the levels of UBE2L6 and its phosphorylation correlate with poor immune infiltration, limited immune and radiation therapy response, and prognosis. Taken together, we demonstrate that RSK1-mediated UBE2L6 phosphorylation and UBE2L6-RNF19A-driven cGAS ubiquitination lead to tumor-intrinsic immune suppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE305014 | GEO | 2026/08/01

REPOSITORIES: GEO

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Project description:Ubiquitination has crucial roles in many cellular processes and dysregulation of ubiquitin machinery enzymes can result in various forms of pathogenesis. Cells only have a limited set of E2 ubiquitin-conjugating enzymes to support the ubiquitination of many cellular targets. As individual E2 enzymes have many different substrates and interactions between E2 enzymes and their substrates can be transient, it is challenging to define all in vivo substrates of an individual E2 and the cellular processes it affects. Particularly challenging in this respect is UBE2D3, a very promiscuous E2 enzyme that affects a broad range of processes. Here, we set out to identify in vivo targets of UBE2D3 by using SILAC-based quantitative ubiquitin diGly proteomics to study global proteome and ubiquitinome changes associated with UBE2D3 depletion. UBE2D3 depletion changed the global proteome, with proteins from metabolic pathways, in particular retinol metabolism, being the most affected. However, the impact of UBE2D3 depletion on the ubiquitinome was much more prominent and, interestingly, identified pathways related to mRNA translation as top pathways being affected. Indeed, we find that ubiquitination of the ribosomal proteins RPS10 and RPS20, critical for ribosome-associated protein quality control (RQC), is dependent on UBE2D3. Moreover, we find that UBE2D3 limits monoubiquitination of histone H2B at lysine 120, mediated by the E3 ligase RNF20. This identifies UBE2D3 as a potential regulator of the diverse and critical cellular processes that are controlled by H2B monoubiquitination. Collectively, our findings show that depletion of an E2 ubiquitin-conjugating enzyme in combination with quantitative diGly-based ubiquitinome profiling is a powerful tool to identify new in vivo E2 substrates, as we have done here for UBE2D3. Together with our identification of RQC factors and H2B as novel in vivo targets of UBE2D3, our work provides an important resource for further studies on the in vivo functions of UBE2D3.

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RSK1 reprograms the ubiquitin pathway to promote immune suppression

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