Fish Herpesvirus KLP Manipulates Beclin1 to Selectively Degrade MITA Through a Precise Autophagic Manner for Immune Evasion

Control of host autophagy acceleration or attenuation has been confirmed in multiple terrestrial animal viruses. Little is known about such mechanisms in aquatic viruses. Here, we report a selective and ingenious autophagy modulation regulated by kinase-like protein (KLP) of cyprinid herpesvirus 2 (CyHV2) to restrict interferon (IFN) production by degrading IFN regulatory factor (IRF) 3 activation (MITA). First, exogenous DNA and RNA-mediated IFN activation were both abrogated by CyHV2 KLP. The common intersection point of MITA with these two signaling pathways was the interaction with KLP. The C terminus of MITA was indispensable for the interaction and was recruited by KLP in subcellular colocalization analysis. Subsequently, we found that KLP degraded MITA in an autophagy-lysosome-dependent manner and, interestingly, individual KLP could not launch host autophagic flow except in the presence of MITA. KLP was also colocalized with the autophagy components Beclin1 and ATG14 and enhanced Beclin1 stability, but not ATG14, through K63-linked polyubiquitination. Finally, KLP significantly decreased the normal state or MITA-enhanced cellular antiviral capacity. These data demonstrated an elaborate autophagic process manipulated by a fish virus only in the presence of the host target, illuminating a mechanism of aquatic viral immune evasion.