Zswim8, the mammalian homolog of EBAX-1, is a cullin-RING E3 ubiquitin ligase. It is involved in target-directed microRNA degradation (TDMD), a pathway crucial for controlling miRNA levels, and also plays roles in protein quality control, myogenesis, and actin cytoskeletal dynamics [1,2,5,7]. TDMD is a post-transcriptional gene regulatory mechanism, and Zswim8 is essential for this process across metazoans [3].

Zswim8-/-embryos in mouse models were smaller, often died near birth, and had lung sacculation and heart ventricular septal defects [4]. These abnormalities were accompanied by aberrant accumulation of over 50 miRNAs, leading to enhanced repression of their mRNA targets [4]. Conditional deletion of Zswim8 in the embryonic nervous system caused global cellular stress, partial perinatal lethality, and defective neural progenitor cell migration, and also impaired spine formation and synaptogenesis in hippocampal neurons [5]. In addition, Zika virus NS5 protein uses Zswim8 as the substrate receptor of Cullin3-RING E3 ligase to degrade STAT2 and inhibit type I interferon signaling [6].

In summary, Zswim8 is vital for embryonic growth, development, and maintaining protein homeostasis in the nervous system. Its functions in TDMD, protein quality control, and myogenesis are essential for normal biological processes. Mouse knockout models have revealed its significance in embryonic development-related diseases and viral-host interactions, providing insights into potential disease mechanisms and therapeutic targets.