KLHL4, a member of the KLHL protein family, is localized on the X chromosome and associates with X-linked cleft palate (CPX) [3]. It can interact with the Cul3 E3 ligase, potentially mediating ubiquitination of interacting proteins. KLHL4 is also a p53 target gene, and its upregulation by p53 may inhibit cell proliferation through activating p21WAF/CDKN1A, a major negative regulator of the cell-cycle [1].

In Klhl4 knocked-out MEF mouse embryonic fibroblasts, they proliferated faster than WT MEF cells, suggesting that Klhl4 has an inhibitory effect on cell proliferation [1]. In vertebrates, the ubiquitin ligase CRL3-KLHL4 restricts signaling of the cytoskeletal regulator CDC42, which is essential for early face, brain, and skin formation. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduces PAK1 ubiquitylation, causing over-activation of CDC42 signaling and defective ectodermal patterning and neurulation [2].

In conclusion, KLHL4 is involved in important biological processes such as cell proliferation regulation and ectodermal development. The study of Klhl4 knockout mouse models has revealed its role in these processes, providing insights into diseases like X-linked cleft palate and potential mechanisms of early embryonic development disorders [1,2,3].