Abstract
In multiple tissues, the Hedgehog secreted morphogen activates in the receiving cells a pathway involved in cell fate, proliferation and differentiation in the receiving cells. This pathway is particularly important during embryogenesis. The protein HHAT (Hedgehog O-acyltransferase) modifies Hh morphogens prior to their secretion, while HHATL (Hh O-acyltransferase-like) negatively regulates the pathway. HHAT and HHATL are homologous to Saccharomyces cerevisiae Gup2 and Gup1, respectively. In yeast, Gup1 is associated with a high number and diversity of biological functions, namely polarity establishment, secretory/endocytic pathway functionality, vacuole morphology and wall and membrane composition, structure and maintenance. Phenotypes underlying death, morphogenesis and differentiation are also included. Paracrine signalling, like the one promoted by the Hh pathway, has not been shown to occur in microbial communities, despite the fact that large aggregates of cells like biofilms or colonies behave as proto-tissues. Instead, these have been suggested to sense the population density through the secretion of quorum-sensing chemicals. This review focuses on Gup1/HHATL and Gup2/HHAT proteins. We review the functions and physiology associated with these proteins in yeasts and higher eukaryotes. We suggest standardisation of the presently chaotic Gup-related nomenclature, which includes KIAA117, c3orf3, RASP, Skinny, Sightless and Central Missing, in order to avoid the disclosure of otherwise unnoticed information.
Highlights
The yeast Saccharomyces cerevisiae is a recognised model to enlighten higher eukaryotic molecular processes, including the ones underlying human pathologies, which are very far from microbial life [1].Intuitively, we associate yeasts, as microbes, to a planktonic form of life
The highly homologous yeast proteins Gup1 and Gup2, discovered by our group in 2000 [19], have two homologues in higher eukaryotes that are responsible for the Hh-secreted morphogen N-terminal palmitoylation (HHAT/Gup2) [20,21] and the negative regulation of the pathway (HHATL/Gup1) [22]
Similarity Analysis of the GUP/HHAT(L) Amino Acid Sequences. Gup proteins from both yeast and higher eukaryotes belong to the membrane bound O-acyltransferase (MBOAT) superfamily of membrane-bound O-acyltransferases, only the mammalian HHAT has been assigned a function as an enzyme performing the palmitoylation of the Sonic Hedgehog ligand [21]
Summary
The yeast Saccharomyces cerevisiae is a recognised model to enlighten higher eukaryotic molecular processes, including the ones underlying human pathologies, which are very far from microbial life [1]. A colony or a biofilm displays a proto-tissue complex behaviour [3] In these communities, cells organise spatially, morphologically and functionally to ensure the survival of the group. Long distance communication between cells is achieved by secreted signalling proteins, namely from the Hedgehog (Hh) or Wingless (Wnt) pathways. The highly homologous yeast proteins Gup and Gup, discovered by our group in 2000 [19], have two homologues in higher eukaryotes that are responsible for the Hh-secreted morphogen N-terminal palmitoylation (HHAT/Gup2) [20,21] and the negative regulation of the pathway (HHATL/Gup1) [22]. We review the information available from S. cerevisiae and from another model yeast, the human commensal/opportunistic pathogen Candida albicans, and complement this with the role of Gup homologues in the regulation of Hedgehog ligand secretion in higher eukaryotes. Data on amino acid sequence comparison throughout model organisms are presented and a harmonising nomenclature is suggested
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