Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation.
The activation of Rab GTPases is a critical focal point of membrane trafficking events in eukaryotic cells; however, the cellular mechanisms that spatially and temporally regulate this process are poorly understood. Here, we identify a null allele of ELP1 as a suppressor of a mutant in a Rab guanine nucleotide exchange factor Sec2p. Elp1p was previously thought to be involved in transcription elongation as part of the Elongator complex. We show that elp1Delta suppression of sec2(ts) is not a result of reduced transcriptional elongation and that Elp1p physically associates with Sec2p. The Sec2p interaction domain of Elp1p is necessary for both Elp1p function and for the polarized localization of Sec2p. Mutations in human Elp1p (IKAP) are a known cause of familial dysautonomia (FD). Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis.
Rahl
Peter B
PB
Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Chen
Catherine Z
CZ
Collins
Ruth N
RN
D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D016764:Cell Polarity; D003593:Cytoplasm / Q000378:metabolism; D004402:Dysautonomia, Familial / Q000235:genetics; D005089:Exocytosis; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D020662:Guanine Nucleotide Exchange Factors; D051548:Histone Acetyltransferases; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010445:Peptide Elongation Factors / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
D020662:Guanine Nucleotide Exchange Factors; D010445:Peptide Elongation Factors; C064456:SEC2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D051548:Histone Acetyltransferases; C479559:IKI3 protein, S cerevisiae; D019204:GTP-Binding Proteins