Abstract
Hedgehog acyltransferase (Hhat), a member of the membrane-bound O-acyltransferase (MBOAT) family, catalyses the covalent attachment of palmitate to the N-terminus of Hedgehog proteins. Palmitoylation is a post-translational modification essential for Hedgehog signalling. This review explores the mechanisms involved in Hhat acyltransferase enzymatic activity, similarities and differences between Hhat and other MBOAT enzymes, and the role of palmitoylation in Hedgehog signalling. In vitro and cell-based assays for Hhat activity have been developed, and residues within Hhat and Hedgehog essential for palmitoylation have been identified. In cells, Hhat promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where Shh palmitoylation occurs. Palmitoylation is required for efficient delivery of secreted Hedgehog to its receptor Patched1, as well as for the deactivation of Patched1, which initiates the downstream Hedgehog signalling pathway. While Hhat loss is lethal during embryogenesis, mutations in Hhat have been linked to disease states or abnormalities in mice and humans. In adults, aberrant re-expression of Hedgehog ligands promotes tumorigenesis in an Hhat-dependent manner in a variety of different cancers, including pancreatic, breast and lung. Targeting hedgehog palmitoylation by inhibition of Hhat is thus a promising, potential intervention in human disease.
Highlights
Hedgehog synthesis and processingHedgehog proteins are a family of secreted, signalling proteins that regulate cell proliferation and tissue patterning during embryonic development [1]
The distribution of fatty acid species attached to Shh can be altered by varying the amount of exogenous fatty acid added to the growth medium [24]. These findings suggest that Hedgehog Acyltransferase (Hhat) is capable of transferring a variety of different fatty acid species to Shh in cells
Treatment with a small-molecule Hhat inhibitor or mutation of H379 within Hhat inhibited palmitoyl-CoA uptake, suggesting that acyltransferase activity and palmitoyl-CoA uptake are linked and coordinated. This is supported by the finding that incorporation of a Shh peptide within the liposome slows palmitoyl-CoA uptake, while a mutant C24A Shh peptide, that cannot be palmitoylated, blocks uptake. These findings suggest that an internal tunnel within Hhat could provide a meeting place for cytosolic palmitoyl-CoA and luminal Shh and thereby serve as a site for Shh palmitoylation
Summary
Hedgehog proteins are a family of secreted, signalling proteins that regulate cell proliferation and tissue patterning during embryonic development [1]. The Hedgehog pathway is mostly shut off in adults, with residual hedgehog signalling providing important support for stem cell maintenance and tissue regeneration. Aberrant over- or re-expression of Hedgehog pathway components in adult tissues is linked to tumorigenesis [3,4]. Shh is the most extensively studied Hedgehog family member and will be used as a model to illustrate Hedgehog protein production and processing [5] (figure 1). Shh is synthesized as a 45 kDa precursor with an N-terminal signal sequence. Upon entry into the endoplasmic reticulum (ER), the signal sequence is cleaved, exposing cysteine as the N-terminal residue. The C-terminal autoprocessing domain royalsocietypublishing.org/journal/rsob Open Biol. 11: 200414
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