Yeast Gup1(2) Proteins Are Homologues of the Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications

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.

Keywords: GUP; HHAT; Hedgehog; morphogenesis; yeast.

Figure 1

Major players implicated in the phenotypes associated with the deletion of GUP1 in S. cerevisiae and C. albicans (grey boxes). Plain arrows indicate established interactions; dashed arrows indicate possible interactions. Pentagons refer to nodal proteins exerting multiple signalling, affecting positively or negatively many other proteins. (A) The Sho1 downward cascade belongs to the HOG (High Osmolarity Glycerol) pathway, and the Rom/Rho cascade constitutes the Cell Wall Integrity—CWI/PKC pathway. Crosstalk between HOG, PKC, the complex lipids and TORC1/2 signalling pathways relevant for GUP1 associated phenotypes is shown; (B) Centrality of Cdc42 phosphorylation (pink boxes) in the control of pathways ultimately promoting differentiation, polarity, growth and reproduction. The central role of one protein shared by many pathways is designated in the text as star-type pathway.

Figure 2

Parallelism between MAPK signalling cascades in yeast and in mammalian cells. In bold: proteins that functionally complement yeast mutants. In orange: proteins that are identical in yeast and mammalian pathways. In blue: proteins involved in the yeast phenotypes affected by GUP1 deletion. Pentagons refer to nodal proteins exerting multiple signalling, affecting positive or negatively many other proteins (star-type pathway). Required nomenclature disambiguation: PAK: P21 Activated Kinase; HPK: Histidine Protein Kinase (Sln1 is also a histidine-aspartate phosphotransferase/kinase); GCK: Germinal Center Kinase; MEKK4 = MTK1.

Figure 3

(A) Key lipid synthesis pathways from S. cerevisiae. In red are shown the types of lipids which amounts are affected by the GUP1 deletion. Steps in GPI anchor synthesis occurring in S. cerevisiae wild-type strain (B) and in gup1∆ mutant (C). Gas1 is an example of a GPI anchored protein that is found excessively liberated into the medium in the mutant cultures. Red arrows indicate the step in which Bosson et al. (2006) suggest that Gup1 acts as an acyltransferase. GPI anchor backbone is composed of mannose (), glucosamine (✩) and ethanolamine-P (☐). Dark thick scrawls represent peptide chains. PI: phosphatidylinositol; IPC: inositol phosphoceramide. Types B, C and D were defined from bands obtained using TLC [136].

Figure 4

Phenotypes associated to the enzymes known to catalyse the steps from PI to PI(4,5)P2 in S. cerevisiae. These phenotypes are also associated with the GUP1 deletion, with the exception of mitophagy. * Preliminary results [45].

Figure 5

Mus musculus HHATL complementation of C. albicans colonies hyphae defect caused by the double deletion of GUP1 alleles [29,156]. Pictures of colony borders were taken after 3 days of incubation in spider medium at 37 °C.

Figure 6

Phenotypes and biological processes associated to the Gup proteins in yeasts (S. cerevisiae and C. albicans) and in the higher eukaryotes M. musculus, H. sapiens and D. melanogaster. Clipart was downloaded from the free access supplier http://etc.usf.edu/clipart/home/.