The DNA repair factor RDM1 as a novel actor in the innate immune response mediated by TLR3 in the endosome: implications for antitumor immunity and cancer therapy

Toll-like receptors (TLRs) are essential components of the innate immune system, acting as sensors for pathogen-associated molecular patterns, as well as a set of self-molecules known as alarmins. Growing evidence indicates that TLRs rely on accessory factors which facilitate ligand recognition and presentation, and potentiate the signalling responses initiated by TLRs. The endosomal double-stranded RNA (dsRNA) sensor TLR3 plays a fundamental role in viral pathogenesis and the control of endogenous retroviruses (ERVs). Here, we present evidence that human RDM1α (RAD52 Motif 1α), a RRM- containing factor previously shown to be involved in the cellular response to the anticancer drug cisplatin, as well as to heat-shock and proteotoxic stress, also operates in the endosome where it interacts with TLR3 in a dsRNA- dependent manner to potentiate TLR3/TRIF innate immune signalling. We found that stimulation of TLR3 requires a structurally conserved dsRNA-binding domain (dsRDB)-like domain in RDM1α. Unlike the previously-described TLR3 coreceptor CLEC18A, which potentiates the production of type I and type III IFNs but not inflammatory cytokines after TLR3 ligand stimulation, RDM1α stimulated both NF-κB and IFN transcriptional pathways activated by TLR3/TRIF in response to poly(I:C). Strikingly, RDM1α was required for efficient expression of antiviral immune genes upon the upregulation of transposable elements elicited by DNA methyltransferase inhibition. RDM1 gene expression displayed cancer-type specificity in relation to antiviral immune response genes, immune cell infiltration and overall survival. Our study identifies RDM1 as a potential target to modulate innate immune signalling, with potential translational implications.