Proteostasis regulation of the centrosomal protein LUZP1, a mediator of Townes-Brocks Syndrome

Abstract

ownes-Brocks Syndrome (TBS) is a rare autosomal dominant genetic disorderlinked to SALL1 gene mutations (SALL1MUT), affecting 1 in 250,000 live births. Itmanifests with distinctive features like dysplastic ears, preaxial polydactyly,imperforate anus, and heart/kidney anomalies. Most TBS-causing mutations resultin de novo stop codons or frameshifts. TBS shares clinical traits with ciliopathies,showing cilia-related defects in patient-derived fibroblasts. LUZP1, identifiedthrough proximity proteomics as a SALL1MUT interactor, is an actin-associatedprotein and ciliogenesis suppressor. TBS cells exhibit reduced LUZP1 levels,degraded by the ubiquitin proteasome system (UPS) likely due to SALL1MUT. Wepropose SALL1MUT interferes with LUZP1 proteostasis, impacting E3 ligase MIB1and DUB enzyme USP21, both crucial for LUZP1 stability. MIB1, a RING-type E3ligase, participates in LUZP1 ubiquitination, while USP21, a centrosome-localizedDUB, contributes to LUZP1 deubiquitination and stability. The interplay betweenMIB1 and USP21 emerges as a pivotal factor in LUZP1 regulation.