Fig. 7: Proposed model.
From: The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
Inactivation of the HUSH component MPP8 leads to increased expression of bidirectionally-transcribed full-length young LINE-1s (L1PA1 and L1PA2), as well as primate-conserved LINE-1s with potential co-opted roles in gene regulation, (some enriched in long non-coding RNAs). Nucleic acid sensing ensues through dsRNA sensors MDA5 and RIG-I, leading to MAVS signaling and activation and secretion of type I IFNs. IFN-α/β then act on the same cells or bystander cells to mediate induction of IFN-stimulated genes through JAK-STAT signaling. MPP8-depletion is also accompanied by DNA damage and is a factor commonly downregulated in cancers, where its decreased mRNA expression is associated with a dominant IFN immune subtype signature.
