Figure 3.

Z‐nucleic acid/ZBP1 interactions are involved in human diseases and antiviral immunity. (A) ZBP1/RIPK3/MLKL pathway is induced by endogenous Z‐nucleic acid in humans and mice. In healthy individuals, Z‐nucleic acid is absent or not accessible to ZBP1; the pathway is not activated and cells survive. In cells of SETDB1‐deficient IBD patients, SETDB1 deficiency leads to genome instability and upregulates endogenous retroelements which act as a possible source of aberrant Z‐nucleic acid to activate ZBP1‐mediated necroptosis. In RIPK1‐deficient mice and PID patients carrying RIPK1‐mutations, the negative regulation of the ZBP1/RIPK3/MLKL pathway is absent, the cells can undergo spontaneous activation of necroptosis which leads to immune disorders and inflammation. (B) The ZBP1/RIPK3/MLKL pathway is activated by exogenous Z‐nucleic acids. Z‐RNAs generated by MCMV and VACV in cytoplasm that activate necroptosis cascade through ZBP1 and this process is blocked by MCMV‐encoding M45 or VACV‐encoding E3, respectively. HSV infection also induces ZBP1‐mediated cell death and the virus employs ICP6 to antagonize this pathway. Influenza A virus produces Z‐RNA that activates ZBP1 in infected nuclei. The downstream MLKL could be recruited for disrupting nuclear envelope or shuttle to cytosol to induce necroptosis.