Midnolin has an ancient origin and negatively regulates type I IFN response in teleost fish

Midnolin has recently been shown to mediate ubiquitin-independent proteasomal degradation of nuclear substrates, yet its evolutionary origin and function in non-mammalian immunity remain largely unexplored. Here, we identify a Midnolin homolog in large yellow croaker (Larimichthys crocea). A key finding is that the origin of Midnolin can be traced back to placozoans, the simplest known animals whose emergence predates that of sponges. In L. crocea, Lcmidnolin expression was significantly upregulated in immune-related tissues upon stimulation with poly(I:C), a viral mimic, suggesting its responsiveness to viral-like signals. Confocal microscopy revealed nuclear localization of LcMidnolin. Functionally, overexpression of LcMidnolin suppressed poly(I:C)-induced activation of type I interferon (IFN) promoters and diminished antiviral gene expression. Consistent with this inhibitory effect, LcMidnolin overexpression impaired the cellular antiviral response, as reflected by increased viral gene expression and exacerbated cytopathic effects in cells infected with spring viremia of carp virus (SVCV). Our findings provide the first evolutionary and functional insights into Midnolin in a non-mammalian vertebrate, revealing its previously unrecognized role as a regulator of the type I IFN signaling pathway.