Dataset Information

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis.

ABSTRACT: The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.

SUBMITTER: Zhang C

PROVIDER: S-EPMC4711834 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis.

Zhang Chunhua C Brown Michelle Q MQ van de Ven Wilhelmina W Zhang Zhi-Min ZM Wu Bin B Young Michael C MC Synek Lukáš L Borchardt Dan D Harrison Reed R Pan Songqin S Luo Nan N Huang Yu-Ming M YM Ghang Yoo-Jin YJ Ung Nolan N Li Ruixi R Isley Jonathan J Morikis Dimitrios D Song Jikui J Guo Wei W Hooley Richard J RJ Chang Chia-En A CE Yang Zhenbiao Z Zarsky Viktor V Muday Gloria K GK Hicks Glenn R GR Raikhel Natasha V NV

Proceedings of the National Academy of Sciences of the United States of America 20151125 1

The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule E ...[more]

PMID: 26607451

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Project description:Background: The eukaryotic endomembrane system most likely arose via paralogous expansions of genes encoding proteins that specify organelle identity, coat complexes and govern fusion specificity. While the majority of these gene families were established by the time of the last eukaryotic common ancestor (LECA), subsequent evolutionary events has moulded these systems, likely reflecting adaptations retained for increased fitness. As well as sequence evolution, these adaptations include loss of otherwise canonical components, the emergence of lineage-specific proteins and paralog expansion. The exocyst complex is involved in late exocytosis and additional trafficking pathways and a member of the complexes associated with tethering containing helical rods (CATCHR) tethering complex family. CATCHR includes the conserved oligomeric Golgi (COG) complex, homotypic fusion and vacuole protein sorting (HOPS)/class C core vacuole/endosome tethering (CORVET) complexes and several others. The exocyst is integrated into a complex GTPase signalling network in animals, fungi and other lineages. Prompted by discovery of Exo99, a non-canonical subunit in the excavate protist Trypanosoma brucei, and availability of significantly increased genome sequence data, we re-examined evolution of the exocyst. Methods: We examined the evolution of exocyst components by comparative genomics, phylogenetics and structure prediction. Results: The exocyst composition is highly conserved, but with substantial losses of subunits in the Apicomplexa and expansions in Streptophyta plants, Metazoa and land plants, where for the latter, massive paralog expansion of Exo70 represents an extreme and unique example. Significantly, few taxa retain a partial complex, suggesting that, in general, all subunits are probably required for functionality. Further, the ninth exocyst subunit, Exo99, is specific to the Euglenozoa with a distinct architecture compared to the other subunits and which possibly represents a coat system. Conclusions: These data reveal a remarkable degree of evolutionary flexibility within the exocyst complex, suggesting significant diversity in exocytosis mechanisms.

Dataset Information

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis.

Publications

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis.

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