STUB1 is an intracellular checkpoint for interferon gamma sensing

Abstract

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNγ) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNγ response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models—with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNγ sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.

Deregulation of interferon-gamma receptor 1 expression and its implications for lung adenocarcinoma progression

“…For example, IFNGR1 can be ubiquitinated by STUB1, an E3 ubiquitin-protein ligase that negatively regulates IFNGR1, thereby reducing IFN-γ sensing. STUB1 depletion increases IFNGR1 abundance and enhances IFN-γ response, promoting an IFN-γ–STAT1–IRF1 axis to induce the activation of genes associated with antigen processing and presentation[ 59 ]. The abundance of IFNGR1 can also be regulated by palmitoylation, leading to accelerated lysosomal degradation of IFNGR1.…”

Interaction with the membrane-anchored protein CHIC2 constrains the ubiquitin ligase activity of CHIP

“…We next wondered what effect CHIC2's inhibitory activity might have on the proteome. CHIP and CHIC2 have been shown to regulate the levels of two members of the cytokine receptor family: interferon gamma receptor (IFNGR) 18,22,23 and a subunit of multiple related cytokine receptors, CSF2RB 24 . These studies suggest that a CHIC2-CHIP complex may primarily regulate recycling and/or turnover of cytokine receptors.…”