Z‐Nucleic Acid Sensing and Activation of ZBP1 in Cellular Physiology and Disease Pathogenesis

ABSTRACT Z‐nucleic acid binding protein 1 (ZBP1) is an innate immune sensor recognizing nucleic acids in Z‐conformation. Upon Z‐nucleic acid sensing, ZBP1 triggers innate immune activation, inflammation, and programmed cell death during viral infections, mice development, and inflammation‐associated diseases. The Zα domains of ZBP1 sense Z‐nucleic acids and promote RIP‐homotypic interaction motif (RHIM)‐dependent signaling complex assembly to mount cell death and inflammation. The studies on ZBP1 spurred an understanding of the role of Z‐form RNA and DNA in cellular and physiological functions. In particular, short viral genomic segments, endogenous retroviral elements, and 3′UTR regions are likely sources of Z‐RNAs that orchestrate ZBP1 functions. Recent seminal studies identify an intriguing association of ZBP1 with adenosine deaminase acting on RNA‐1 (ADAR1), and cyclic GMP‐AMP synthase (cGAS) in regulating aberrant nucleic acid sensing, chronic inflammation, and cancer. Thus, ZBP1 is an attractive target to aid the development of specific therapeutic regimes for disease biology. Here, we discuss the role of ZBP1 in Z‐RNA sensing, activation of programmed cell death, and inflammation. Also, we discuss how ZBP1 coordinates intracellular perturbations in homeostasis, and Z‐nucleic acid formation to regulate chronic diseases and cancer.