Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling

Abstract

IntroductionProteasome inhibition is first line therapy in multiple myeloma (MM). The immunological potential of cell death triggered by defects of the ubiquitin-proteasome system (UPS) and subsequent perturbations of protein homeostasis is, however, less well defined.MethodsIn this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD).ResultsOur data show that while BTZ treatment triggers sterile type I interferon (IFN) responses, exposure of the cells to ONX0914 or RA190 was mostly immunologically silent. Interestingly, inhibition of protein de-ubiquitination by PR619 was associated with the acquisition of a strong type I IFN gene signature which relied on key components of the unfolded protein and integrated stress responses including inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR) and general control nonderepressible 2 (GCN2). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms.ConclusionAltogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.

Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals

“…First, Nrf1, a transcription factor homologous to SKN‐1A, also upregulates the expression of proteasome subunits in response to proteasome blockade in this host. [ 91 ] In the second response, blockade of the proteasome induces the IFN‐I response, [ 92 ] similar to how it induces the IPR in worms. Moreover, mutations in the proteasome are associated with inflammatory disorders called interferonopathies that are characterized by overexpression of IFN‐I.…”

Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans

“…While proteasome-mediated suppression of inflammatory/immune responses might be an evolutionarily conserved phenomenon, the exact mechanisms of how immune responses are kept in check are likely to differ. For example, activation of type-I interferon signaling in mammals as a consequence of proteasome dysfunction has been attributed to ER stress and activation of the unfolded protein response (UPR) [ 28 , 50 , 51 ]. This is unlikely to be the case in the context of oomycete recognition as we have previously shown that introducing ER stress does not induce chil-27p :: GFP [ 2 ].…”