ZNFX1

NFX1-type zinc finger-containing protein 1

RNA-activated non-canonical E3 ubiquitin ligase required for cell survival during interferon (IFN) responses. Functions as an ATP-dependent 5'-> 3' RNA translocase that selectively recognizes long single-stranded RNA (ssRNA) molecules (>100 nt) from viral or host origin during immune activation. Upon ssRNA binding, oligomerizes to assemble a split E3 active site in trans, involving the Z-RING domain that binds and activates E2-ubiquitin conjugates, such as UBE2D2, and the RZ catalytic domain that mediates ubiquitin transfer. Catalyzes hydroxyl ubiquitination of the 2'-OH of ssRNA ribose and auto-ubiquitination, generating mainly 'Lys-48'- and 'Lys-6'-linked polyubiquitin chains (PubMed:40876457). Forms ubiquitin-coated RNA condensates and stress granules, thereby regulating RNA metabolism, limiting excessive immune signaling, and preventing IFN-induced cell death (PubMed:33872655, PubMed:40876457). Also required for immunity against some bacteria, such as mycobacteria (PubMed:33876776). Inhibits NLRP3 inflammasome activation by sequestering NLRP3 in the cytoplasm and preventing its translocation to trans-Golgi network vesicles during the resting state. Upon inflammasome activation, is cleaved by CASP1, establishing a feed-forward loop that amplifies NLRP3 inflammasome activity (PubMed:39333773)