FBXO38 Ubiquitin Ligase Controls Centromere Integrity via ZXDA/B Stability

Alterations in the gene encoding the E3 ubiquitin ligase substrate receptor FBXO38 have been associated with several diseases, including early-onset motor neuronopathy. However, the cellular processes affected by the enzymatic action of FBXO38 are not yet known. Here, we identify the zinc finger proteins ZXDA/B as its interaction partners. FBXO38 controls the stability of ZXDA/B proteins via ubiquitination and proteasome-dependent degradation. We show that ZXDA/B proteins associate with the centromeric protein CENP-B and that the interaction between ZXDA/B and FBXO38 or CENP-B is mutually exclusive. Functionally, ZXDA/B factors control the protein level of chromatin-associated CENP-B. Furthermore, their inappropriate stabilization leads to upregulation of CENP-A and CENP-B positive centromeric chromatin. Thus we demonstrate a previously unknown role of cullin-dependent protein degradation in the control of centromeric chromatin integrity.

Automated summary

The gene encoding FBXO38, an E3 ubiquitin ligase substrate receptor, has been found to be associated with various diseases. The study shows that FBXO38 controls the stability of ZXDA/B proteins through ubiquitination and proteasome-dependent degradation. These ZXDA/B proteins are involved in the regulation of chromatin-associated CENP-B protein levels, and their inappropriate stabilization leads to upregulation of CENP-A and CENP-B in centromeric chromatin.