Dispatching plasma membrane cholesterol and Sonic Hedgehog dispatch: two sides of the same coin?

Abstract

Vertebrate and invertebrate Hedgehog (Hh) morphogens signal over short and long distances to direct cell fate decisions during development and to maintain tissue homeostasis after birth. One of the most important questions in Hh biology is how such Hh signaling to distant target cells is achieved, because all Hh proteins are secreted as dually lipidated proteins that firmly tether to the outer plasma membrane leaflet of their producing cells. There, Hhs multimerize into light microscopically visible storage platforms that recruit factors required for their regulated release. One such recruited release factor is the soluble glycoprotein Scube2 (Signal sequence, cubulin domain, epidermal-growth-factor-like protein 2), and maximal Scube2 function requires concomitant activity of the resistance-nodulation-division (RND) transporter Dispatched (Disp) at the plasma membrane of Hh-producing cells. Although recently published cryo-electron microscopy-derived structures suggest possible direct modes of Scube2/Disp-regulated Hh release, the mechanism of Disp-mediated Hh deployment is still not fully understood. In this review, we discuss suggested direct modes of Disp-dependent Hh deployment and relate them to the structural similarities between Disp and the related RND transporters Patched (Ptc) and Niemann-Pick type C protein 1. We then discuss open questions and perspectives that derive from these structural similarities, with particular focus on new findings that suggest shared small molecule transporter functions of Disp to deplete the plasma membrane of cholesterol and to modulate Hh release in an indirect manner.

Two-way Dispatched function in Sonic hedgehog shedding and transfer to high-density lipoproteins

“…The second is that Shh self-assembly by the law of mass action 46 is also not supported, because this process should solubilize Shh regardless of the presence or absence of serum. In contrast, one function of Disp is to extract and transfer plasma membrane cholesterol to a soluble sink to transport it away from the cell 4, 47 . In vertebrates, HDLs represent soluble sinks for “free” peripheral cholesterol 48 , and HDLs as well as the pharmacological cholesterol chelator methyl--cyclodextrin (m cd) were previously shown to increase Shh shedding 4, 23, 49 .…”

Hedgehog on the Move: Glypican-Regulated Transport and Gradient Formation in Drosophila

“…An important component of Hh signalling required for the release of cholesterol-modified Hh from producing cells is Disp; a 12-span transmembrane protein with a sterol sensing domain (SSD) similar to that of Ptc and proteins involved in sterol homeostasis and transport such as Niemann-Pick disease, type C1 (NPC1) and Sterol regulatory element binding protein cleavage activating protein (SCAP) [ 105 , 106 ]. Consistent with the presence of SSDs in these proteins, Ptc has recently been shown to transport free membrane cholesterol from the inner plasma membrane leaflet to an unknown acceptor [ 107 ], and Disp also depletes the plasma membrane of free cholesterol [ 105 ], but can also transfer the cholesteroylated C-terminal Hh peptide to soluble acceptors of the high-density lipoprotein (HDL) family [ 108 ].…”

Hedgehog on the Move: Glypican-Regulated Transport and Gradient Formation in Drosophila

“…An important component of Hh signalling required for the release of cholesterolmodified Hh from producing cells is Disp; a 12-span transmembrane protein with a sterol sensing domain (SSD) similar to that of Ptc and proteins involved in sterol homeostasis and transport such as Niemann-Pick disease, type C1 (NPC1) and Sterol regulatory element binding protein cleavage activating protein (SCAP) [105,106]. Consistent with the presence of SSDs in these proteins, Ptc has recently been shown to transport free membrane cholesterol from the inner plasma membrane leaflet to an unknown acceptor [107], and Disp also depletes the plasma membrane of free cholesterol [105], but can also transfer the cholesteroylated C-terminal Hh peptide to soluble acceptors of the high-density lipoprotein (HDL) family [108].…”