SEM1, a homologue of the split hand split foot malformation candidate geneDss1, regulates exocytosis and pseudohyphal differentiation in yeast

The exocyst is an essential multiprotein complex mediating polarized secret ion in yeast. Here we describe a gene, SEMI, that can multicopy-suppress ex ocyst mutants sec3-2, sec8-9, sec10-2, and sec15-1. SEMI is highly conserve d among eukaryotic species. Its human homologue, DSS1, has been suggested a s a candidate gene for the split hand/split foot malformation disorder. SEM I is not an essential gene. However, its deletion rescued growth of the tem perature-sensitive exocyst mutants sec3-2, sec8-9, sec10-1, and sec15-1 at the restrictive temperature, Cell fractionation showed that Sem1p is mainly cytosolic but also associates with the microsomal fraction. In linear sucr ose gradients, Sem1p cosedimented with the exocyst component Sec8p, In dipl oid cells that normally do not form pseudohyphae (S288C background), deleti on of SEMI triggered pseudohyphal growth. This phenotype was abolished afte r reintroduction of either SEM1 or the mouse homologue Dss1 into the cells. In diploids that have normal capacity for pseudohyphal growth (Sigma 1278b background), deletion of SEM1 enhanced filamentous growth. The functionali ty of both SEMI and Dss1 in a differentiation process in yeast suggests tha t Dss1 indeed could be the gene affected in the split hand/split foot malfo rmation disorder. These results characterize SEMI as a regulator of both ex ocyst function and pseudohyphal differentiation and suggest a unique link b etween these two cellular functions in yeast.