LUZP1 and the tumour suppressor EPLIN are negative regulators of primary cilia formation

Abstract

Running title: LUZP1 and EPLIN regulate ciliogenesis SUMMARY Gonçalves et al. show that LUZP1 and its interactor EPLIN are negative regulators of ciliogenesis. LUZP1 is a novel actin-stabilizing protein localizing at the centrosome and basal body where it may regulate actin-associated processes. 2 ABSTRACT Cilia/flagella are microtubule-based cellular projections with important sensory and motility functions. Their absence or malfunction is associated with a growing number of human diseases collectively referred to as ciliopathies. However, the fundamental mechanisms underpinning cilia biogenesis and functions remain only partly understood. Here, we show that LUZP1, and its interacting protein EPLIN, are negative regulators of primary cilia formation. LUZP1 is an actinassociated protein that localizes to both actin filaments and the centrosome/basal body. Like EPLIN, LUZP1 is an actin-stabilizing protein and likely regulates actin dynamics at the centrosome. Both proteins interact with ciliogenesis and cilia length regulators, and are potential players in the actin-dependent processes involved in centrosome to basal body conversion. Ciliogenesis deregulation caused by LUZP1 or EPLIN loss may contribute to the pathology of their associated diseases.

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome

“…Two independent proximity labeling studies identified LUZP1 as a proximal interactor of centriole ( Gupta et al, 2015 ) and centriolar satellite-related proteins ( Gheiratmand et al, 2019 ). Moreover, LUZP1 has been recently reported as a centrosomal protein involved in cilia regulation ( Gonçalves et al, 2019 ). These localizations are also consistent with fluorescent LUZP1 fusion proteins (this work; [ Gupta et al, 2015 ; Gonçalves et al, 2019 ] #117).…”

“…Moreover, LUZP1 has been recently reported as a centrosomal protein involved in cilia regulation ( Gonçalves et al, 2019 ). These localizations are also consistent with fluorescent LUZP1 fusion proteins (this work; [ Gupta et al, 2015 ; Gonçalves et al, 2019 ] #117). Discrepancies with the previously reported LUZP1 localization and distribution might be due to technical differences, such as epitope specificity for the antisera used in the immunohistochemistry.…”

A Proximity Mapping Journey into the Biology of the Mammalian Centrosome/Cilium Complex

“…To date, proximity mapping has been used to mechanistically dissect these processes using both targeted and systematic approaches. As for the targeted approaches, proximity interaction maps were generated for known regulators of cilium assembly as well as proteins mutated in ciliopathies including CEP72, CCDC66, CEP104, MIB1, ARL13B, CDC14A, LUZP1 and CEP120 [122,129,130,132,[134][135][136]151]. As with centriole duplication, these maps identified new functional modules required for specific steps of cilium assembly and revealed mechanisms that underlie ciliopathies.…”

“…Another new discovery unveiled from proximity mapping is the regulatory relationship between the actin cytoskeleton and ciliogenesis. The actin-stabilizing protein LUZP1 and its interactor SALL1 had proximity interactions with centrosome and cilium proteins [134,135,139]. Their further characterization identified them as regulators of cilium assembly and Hedgehog signaling, and suggested mechanisms that underlie the Townes-Brocks syndrome.…”

Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis

“…LUZP1 encodes a ciliary basal body protein that has recently been shown to play important roles in regulating ciliogenesis. 45,46 While there is no Mendelian disease yet known to result from disruption of the LUZP1 gene, recent work has shown reduced LUZP1 expression in fibroblasts derived from Townes-Brockes syndrome (characterized by renal disease, among other findings) patients, 47 suggesting that LUZP1 may play a role in the pathogenesis of this disorder.…”