Toste Rego, A. | bioRxiv Science

bioRxiv2021

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumors responses to immunotherapy. For example, immunoproteasomes - a subset of proteasomes induced by inflammatory signals - may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/464690v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e87910org.highwire.dtl.DTLVardef@641843org.highwire.dtl.DTLVardef@175092corg.highwire.dtl.DTLVardef@ad34c2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMapping the degradation landscape in Non-Small Cell Lung Cancer (NSCLC) uncovers altered proteasome activity and composition C_LIO_LIProteasome regulator PSME4 plays an anti-inflammatory role in NSCLC by attenuating immunoproteasome activity C_LIO_LIPSME4 restricts tumor antigen presentation and cytokine secretion, defining a cold tumor environment C_LIO_LIPSME4 drives tumor immune evasion and is associated with resistance to immunotherapy C_LI

cancer biology↗

bioRxiv2021

New insights into the human 26S proteasome function and regulation

The 26S proteasome is a protease complex essential for proteostasis and strict regulation of diverse critical physiological processes, the mechanisms of which are still not fully described. The human 26S proteasome purification was optimized without exogenous nucleotides, to preserve the endogenous nucleotide occupancy and conformation of its AAA-ATPase subunits. This unveiled important effects on the proteasome function and structure resulting from exposure to Ca2+ or Mg2+, with important physiological implications. This sample, with an added model degron designed to mimic the minimum canonical ubiquitin signal for proteasomal recognition, was analysed by high-resolution cryo-EM. Two proteasome conformations were resolved, with only one capable of degron binding. The structural data show that this occurs without major conformation rearrangements and allows to infer into the allosteric communication between ubiquitin degron binding and the peptidase activities. These results revise existing concepts on the 26S proteasome function and regulation, opening important opportunities for further research.

biochemistry↗