Elp1p, the Yeast Homolog of the FD Disease Syndrome Protein, Negatively Regulates Exocytosis Independently of Transcriptional Elongation

Abstract

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.

Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes

“…8 A cytoplasmic role of Elongator complex was suggested from the finding that Elp1p interacted with Sec2p, a protein required for polarized transport of secretory vesicles to the bud tip in S. cerevisiae. 9 Transport of secretory vesicles requires the guanine nucleotide exchange factor Sec2p for activation of the vesicleassociated GTPase Sec4p. 10,11 Sec2p associates with Elp1p and it was proposed that the Elongator complex is required for regulation of exocytosis by influencing localization of Sec2p.…”

“…10,11 Sec2p associates with Elp1p and it was proposed that the Elongator complex is required for regulation of exocytosis by influencing localization of Sec2p. 9 A different nuclear function described for the Elongator complex was in telomeric gene silencing and DNA repair as Elongator mutants display partial loss of telomeric gene silencing and increased sensitivity to DNA damage agents. 12 In addition to the HAT domain, the Elp3p subunit of the Elongator complex shares sequence homology to proteins from the Radical S-adenosylmethionine (SAM) superfamily, proteins harboring an ironsulfur cluster that catalyze a variety of radical reactions using SAM.…”

“…12 In exocytosis, an interaction between Elp1p and Sec2p was proposed to be important for correct polarized localization of Sec2p. 9 An explanation for the dependence of the mcm 5 s 2 U 34 nucleoside is that it promotes a canonical anticodon loop conformation which stabilize codon-anticodon interaction. 29,30 Additional support that elevated levels of hypomodified tRNA correct phenotypes observed in mutants with defects in wobble uridine modifications came from experiments in Schizosaccharomyces pombe.…”

Elongator orchestre la neurogenèse du cortex cérébral

“…En effet, le complexe Elongator, et plus particulièrement sa sous-unité Elp3, possède une activité histone acétyl-transférase envers l'histone H3, rendant ainsi possible la progression de l'ARN polymérase II au niveau de la région transcrite de certains gènes [4,5]. Des études récentes ont démontré qu'Elongator remplit aussi des fonctions dans le cytoplasme, comme la régulation de l'exocytose et la modification de certains ARN de transfert [6,7].…”

Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells

“…These observations combined with reports showing an association of Elongator with several nascent RNAs in yeast [8] and with the preferential recruitment of Elongator to the transcribed regions of human genes [9][10][11], strongly support a role for Elongator in transcriptional elongation. Meanwhile, other reports also provided experimental evidence for a role of Elongator in exocytosis and tRNA modification [12][13][14]. Still and although these reports brought significant insights regarding the biological roles of Elongator, it is currently unclear whether this complex harbours multiple functions in distinct cell compartments or whether a single function indirectly regulates the others [15].…”