An autophagic team – July 2014 CFATG
An autophagic team – July 2014
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Intracellular traffic, macromolecular complexes and cancer

Institut de Cancérologie Gustave Roussy
CNRS UMR 8126
114, rue Edouard Vaillant
94805 Villejuif
Tel. office: +33(0)1 42 11 48 53
Tel. lab: +33(0)1 42 11 49 20
Fax: +33(0)1 42 11 54 94
e-mail: svetlana.dokudovskaya@igr.fr

Presentation of the team:

Web site : http://www.gustaveroussy.fr/fr/page/-trafic-membranaire-complexes-
macromoleculaire-et-cancer_3789

Team Leader:

Svetlana Dokudovskaya, CR1 CNRS, svetlana.dokudovskaya@igr.fr

Team Members:

Claire Martel-Jantin, post-doctoral fellow
Yinxing Ma, PhD student, Université Paris-XI

team-july2014
From left to right : Claire Martel-Jantin, Svetlana Dokudovskaya, Yinxing Ma

Key words : TORC1, SEA complex, autophagy

Research Topic:

The highly conserved Target of Rapamycin Complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses. In rich nutrient environment TORC1 promotes anabolic processes, including ribosome biogenesis and translation. Nutrient limitation or treatment with rapamycin inhibits the Tor1 kinase and initiates autophagy – a catabolic process that mediates degradation and recycling of cytoplasmic components. The nutrient sensing function of TORC1 is not fully understood and the mechanisms of TORC1 modulation by amino acid and nitrogen availability are not yet clear.

Recently our team in collaboration with other laboratories discovered and characterized multiprotein SEA complex in yeast S.cerevisiae. The SEA acts upstream of the TORC1 and is implicated in the regulation of both general and specific forms of autophagy. The Sea proteins contain structural elements present in intracellular structural trafficking complexes. We uncover an entirely new set of key TORC1 functions, which are under the control of the SEA complex such as TORC1 localization and vacuole fragmentation. Due to its structural and functional characteristics the SEA complex emerges as a platform that can coordinate both structural and enzymatic activities necessary for the effective functioning of the TORC1.

The SEA complex is conserved from yeast to human and its function in the regulation of the TORC1 pathway is also preserved. Interestingly, several SEA components in human have been characterized as tumor suppressors and also involved in the cellular response to anticancer drug treatments.

Our team is currently working on the SEA complex both in the yeast and human non-tumor and oncogenic cell lines. Our goal is to study the molecular basis of the SEA function in the regulation of the TORC1 pathway, autophagy and cancer.

Fig-teamJuly2014
An overview of the yeast SEA complex activities and interactions. The SEA complex is composed of two subcomplexes – SEACAT (activates TORC1) and SEACIT (inhibits TORC1). The SEA complex is situated at the vacuole membrane and interacts with V-ATPase, mitochondrion, TORC1 (straight blue arrows). SEA complex possess GAP activity (curved blue arrow) towards another TORC1 regulator – EGO complex. Both SEA and EGO act upstream of the TORC1 (curved red arrows). Deletions of the SEACIT members activate TORC1 and inhibit autophagy.

Main Publications:

• Algret R., Fernandez-Martinez J., Shi Y., Kim S.J., Pellarin R., Cimermancic, Cochet E., Sali A., Chait B.T, Rout M.P and Dokudovskaya S. Molecular Architecture and Function of the SEA Complex – a Modulator of the TORC1 Pathway. Mol. Cell. Proteomics. Submitted.
• Algret R. and Dokudovskaya S. The SEA complex – the beginning. Biopolymers and Cell (2012). Vol.28., N4. p.281-284.
• Dokudovskaya S, Rout MP. A novel coatomer−related SEA complex dynamically associates with the vacuole in yeast and is implicated in the response to nitrogen starvation. Autophagy. 2011 Nov 1;7(11):1392−3. Epub 2011 Nov 1.
• Dokudovskaya S, Waharte F, Schlessinger A, Pieper U, Devos DP, Cristea IM, Williams R, Salamero J, Chait BT, Sali A, Field MC, Rout MP, Dargemont C., (2011). A conserved coatomer−related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol. Cell. Proteomics. 2011 Jun;10(6):M110.006478. Epub 2011 Mar 31.
• Alber F.*, Dokudovskaya S.*, Veenhoff L.*, Zhang W., Kipper J., Devos D., Suprapto A., Karni-Shmidt O., Williams R., Chait B.T., Sali A., Rout M.P. The molecular architecture of the nuclear pore complex. * – equal contribution. Nature, 2007, 450, 695-701
• Alber F., Dokudovskaya S.*, Veenhoff L.*, Zhang W., Kipper J., Devos D., Suprapto A., Karni-Shmidt O., Williams R., Chait B.T., Rout M.P., Sali A. Determining the architectures of macromolecular assemblies. * – equal contribution. Nature, 2007, 450, 683-694

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