The hydrolethalus syndrome protein HYLS-1 links core centriole structure to cilia formation

Abstract

Centrioles are subcellular organelles composed of a ninefold symmetric microtubule array that perform two important functions: (1) They build centrosomes that organize the microtubule cytoskeleton, and (2) they template cilia, microtubule-based projections with sensory and motile functions. We identified HYLS-1, a widely conserved protein, based on its direct interaction with the core centriolar protein SAS-4. HYLS-1 localization to centrioles requires SAS-4 and, like SAS-4, HYLS-1 is stably incorporated into the outer centriole wall. Unlike SAS-4, HYLS-1 is dispensable for centriole assembly and centrosome function in cell division. Instead, HYLS-1 plays an essential role in cilia formation that is conserved between Caenorhabditis elegans and vertebrates. A single amino acid change in human HYLS1 leads to a perinatal lethal disorder termed hydrolethalus syndrome, and we show that this mutation impairs HYLS-1 function in ciliogenesis. HYLS-1 is required for the apical targeting/anchoring of centrioles at the plasma membrane but not for the intraflagellar transport-dependent extension of the ciliary axoneme. These findings classify hydrolethalus syndrome as a severe human ciliopathy and shed light on the dual functionality of centrioles, defining the first stably incorporated centriolar protein that is not required for centriole assembly but instead confers on centrioles the capacity to initiate ciliogenesis.[Keywords: Centrioles; basal bodies; ciliogenesis; hydrolethalus syndrome; ciliopathy] Supplemental material is available at http://www.genesdev.org.

The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate

“…All three mutants carry large deletions in their coding region and are putative null alleles (Supplementary Fig 1a)33. In C. elegans , the head amphid and tail phasmid cilia take up lipophilic fluorescent dye from the external environment39.…”

A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis

“…BBs are localized to the dendritic tips, thus ensuring cilia formation at this location. Unlike in mammals, BBs in C. elegans are thought to degenerate or remodel following initiation of ciliogenesis in embryos (Dammermann et al, 2009; Perkins et al, 1986). However, early steps of ciliogenesis have not been visualized in C. elegans , and the mechanisms regulating BB positioning in sensory neurons remain uncharacterized in this organism.…”

Ciliogenesis inCaenorhabditis elegansrequires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins

“…elegans cilia are located on the distal dendritic endings of sensory neurons, where a centriole-derived complex consisting principally of transition fibers (TF) precedes the microtubulebased axoneme (Dammermann et al, 2009;Perkins et al, 1986). The first segment of the axoneme is the transition zone (TZ), a region where many ciliary proteins congregate, either regulating ciliary traffic, being imported or exported into the cilium, or playing structural and functional roles essential for ciliogenesis and formation of the so-called ciliary gate (Rosenbaum and Witman, 2002).…”