RSK1 reprograms the ubiquitin pathway to promote immune suppression

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.