Klhl18, Kelch-like protein 18, is a BTB domain-containing protein that binds to cullin 3 (CUL3) to form a ubiquitin ligase complex. This complex is involved in multiple biological pathways such as ubiquitination-mediated protein degradation, which is crucial for maintaining normal cellular functions [2,4].

In Klhl18-deficient mice, several phenotypes are observed. In rod photoreceptors, Klhl18-/-mice show decreased rod light responses and mislocalization of the transducin α-subunit (Tα) in the dark, indicating its role in light-dark adaptation. Cul3-Klhl18 promotes ubiquitination and degradation of Unc119, a Tα-interacting protein, and phosphorylation affects this process [1]. In non-small cell lung cancer (NSCLC) cells, overexpressing Klhl18 inhibits cell proliferation, migration, and invasion by promoting ubiquitination and degradation of phosphatidylinositol 3-kinase (PI3K) p85α and inhibiting PD-L1 expression [2]. Klhl18 mutant mice also display progressive, predominantly low-frequency recessive hearing impairment due to inner hair cell dysfunction, suggesting its necessity for maintaining inner hair cell stereocilia and normal function at low frequencies [3]. Depletion of CUL3 and KLHL18 in cells causes a delay in mitotic entry, and the CUL3-KLHL18 ligase ubiquitylates Aurora-A, which is required for timely mitotic entry [4].

In conclusion, Klhl18 is essential for various biological processes. Its functions in light-dark adaptation in photoreceptors, regulation of NSCLC cell behavior, maintenance of inner hair cell function for hearing, and control of mitotic entry are well-demonstrated through mouse models and cell-based studies. These findings have significant implications for understanding diseases related to vision, cancer, hearing, and cell cycle regulation [1,2,3,4].