Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Abstract

Hedgehog (Hh) signaling is essential during development and in organ physiology. In the canonical pathway, Hh binding to Patched (PTCH) relieves the inhibition of Smoothened (SMO). Yet, PTCH may also perform SMO-independent functions. While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe non-canonical PTCH function. Here, we show that PTC-3 is a cholesterol transporter. ptc-3(RNAi) leads to accumulation of intracellular cholesterol and defects in ER structure and lipid droplet formation. These phenotypes were accompanied by a reduction in acyl chain (FA) length and desaturation. ptc-3(RNAi)-induced lethality, fat content and ER morphology defects were rescued by reducing dietary cholesterol. We provide evidence that cholesterol accumulation modulates the function of nuclear hormone receptors such as of the PPARα homolog NHR-49 and NHR-181, and affects FA composition. Our data uncover a role for PTCH in organelle structure maintenance and fat metabolism.

Hedgehog lipids: Promotors of alternative morphogen release and signaling?

“…In functional terms, it is currently thought that ligand-free Ptc (Figure 1, step 6) forms a trimer [23] that undergoes conformational cycling to actively pump cholesterol from the inner leaflet of the plasma membrane to hand it off to extracellular sterol acceptors. [24,25] Consistent with such a highly conserved cholesterol transporter function of Ptc, [26] detection of four collective sterolbinding sites (S1-S4) in Ptc suggest a central hydrophobic conduit for cholesterol transport that courses from the inner leaflet of the plasma membrane to the extracellular domain [24,27,28] (Figure 1 bottom row, far right). Through this conduit, the amount of membrane cholesterol is continuously reduced but increases rapidly upon Hh binding to Ptc.…”

“…[29] The other model of Scube2-modulated Shh shedding requires that the role of Disp in Hh release must be indirect, possibly involving a Disp-modulated messenger molecule that in turn affects shedding. This messenger molecule might be plasma membrane cholesterol, as indicated by the known structural similarities between Disp and the established cholesterol pumps Ptc [26,29] and NPC1. [75] Further support for a sterol-pumping function of Disp comes from the detection of sterol-like densities in the Disp transmembrane domains, [72,76] again similar to what has been described for Ptc [28,29] and NPC1.…”

Meta-Analysis of Caenorhabditis elegans Transcriptomics Implicates Hedgehog-Like Signaling in Host-Microbe Interactions

“…Interactions between fatty acid metabolism and innate immunity ( Anderson and Pukkila-Worley, 2020 ) or between fatty acid metabolism and Hedgehog-like signaling ( Lin and Wang, 2017 ; Del Castillo et al, 2021 ) have been frequently reported in animals, including in C. elegans . Increased C. elegans fatty acid metabolism is also strongly associated with reproduction ( Ezcurra et al, 2018 ), while a trade-off between reproduction and the mounting of effective innate immune responses has been previously established ( TeKippe and Aballay, 2010 ).…”

“…(they became hypersensitive to thermal stress, Figure 3C ). Lipid metabolism is key to both immunity and the HHLS pathway since phospholipid membrane dynamics and cholesterol metabolism are critical to Hedgehog signaling (Cadena Del Castillo et al, 2021 ). Our data also suggest that grl-21 contributes to worm resistance to E. faecalis infection, together with related HRPs grl-6, grl-12, grl-22 , and grl-27 ( Figures 3B,C ), although they do not point out to specific cognate PTR receptors.…”

“…Although the worm genome expresses a single Gli homolog (TRA-1) primarily involved in sex-determination ( Hodgkin and Brenner, 1977 ; Hodgkin, 1987 ; Ellis, 2020 ), the nematode HHLS pathway lacks the canonical Hedgehog intracellular transduction pathway, and the evolutionary function of the PTR and HRP family expansions remains unclear ( Baker et al, 2021 ). HHLS genes have been involved in C. elegans epithelial function and development ( Hao et al, 2006a ; Liegeois et al, 2006 ; Soloviev et al, 2011 ), cuticular structure and patterning ( Zugasti et al, 2005 ; Hao et al, 2006b , c ; Liegeois et al, 2006 ; Kouns et al, 2011 ; Chiyoda et al, 2021 ; Cohen et al, 2021 ), sensory organ formation ( Michaux et al, 2000 ; Liegeois et al, 2007 ; Oikonomou et al, 2011 ; Wang et al, 2017 ; van der Burght et al, 2020 ), neurogenesis ( Kume et al, 2019 ) and axonal guidance ( Riveiro et al, 2017 ), immunity ( Roberts et al, 2010 ; Lightfoot et al, 2016 ), lipid homeostasis ( Lin and Wang, 2017 ; Del Castillo et al, 2021 ), reproduction ( Kuwabara et al, 2000 ; Templeman et al, 2020 ), and longevity ( Ji et al, 2021 ). In particular, the HHLS pathway was found to mediate the impact of microbial metabolites on host lipid metabolism ( Lin and Wang, 2017 ), supporting a direct role in host-nematode interactions that could in part explain the diversification of HRP ligands and PTR receptors.…”