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LUBI

Regulation and function of linear ubiquitination by HOIP

Coordinatore	INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Austria [AT]
Totale costo	1˙997˙908 €
EC contributo	1˙997˙908 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2013-CoG
Funding Scheme	ERC-CG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-07-01 - 2019-06-30

Partecipanti

#	participant	country	role	EC contrib. [€]
1	INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH Organization address address: Dr Bohrgasse 3 city: VIENNA postcode: 1030 contact info Titolo: Dr. Nome: Fumiyo Cognome: Ikeda Email: send email Telefono: +43 179044 4900 Fax: +43 179044 224900	AT (VIENNA)	hostInstitution	1˙997˙908.00
2	INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH Organization address address: Dr Bohrgasse 3 city: VIENNA postcode: 1030 contact info Titolo: Mrs. Nome: Tanja Cognome: Winkler Email: send email Telefono: +43 179044 4410 Fax: +43 179871 53	AT (VIENNA)	hostInstitution	1˙997˙908.00

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functions protein signalling substrates sharpin shown elucidate lubac recently mice ub yet inflammation ubiquitination linear nf ligase kb roles regulatory diseases chain ubiquitin human hoil catalytic l biological subunits hoip drosophila

Obiettivo del progetto (Objective)

'Ubiquitin (Ub) is a small protein modifier, regulating diverse biological functions such as signalling, DNA repair and proteasomal degradation. Ub can form polymers via 7 Lys residues of Ub itself. Recently, we have discovered that an E3 ligase complex, Linear Ubiquitin chain Assembly Complex (LUBAC) generates a novel type of Ub polymer linked via Met-1, ‘linear Ub chain’ and regulates NF-kB signalling in mice. Because linear Ub is unique and the study of it is still in infancy, the only E3 ligase known is LUBAC, comprising a catalytic protein HOIP, and two regulatory subunits SHARPIN and HOIL-1L. We have shown that SHARPIN deficiency leads inflammation in mice. A mutation in HOIL-1L gene of human was shown to lead immunodeficiency. Yet, the regulatory mechanisms of HOIP catalytic activity and the biological implications remain poorly understood. Here, we aim to

- Elucidate the roles of HOIP in Drosophila - Elucidate the roles of ubiquitination and ligase activities of mammalian HOIP in vivo - Identify novel substrates of human HOIP and clarification of their roles

We recently identified an orthologue of HOIP in Drosophila, yet its genome does not encode SHARPIN or HOIL-1L. We aim to elucidate how dmHOIP mediates linear ubiquitination in the absence of regulatory subunits and the roles of HOIP in the NF-kB signalling by genetically deleting HOIP in Drosophila. We further aim to elucidate the role of HOIP E3 ligase activity and ubiquitination in inflammation by generating the conditional knockin mice of HOIP mutants. Moreover, we will develop a protein chip assay to identify new substrates of HOIP and determine how they contribute to the biological functions.

Since Ub plays such a wide variety of pathological functions including cancer, inflammation and neuronal diseases, I believe the expected results not only will lead to a better understanding of functional role of HOIP but will also identify novel aspects of linear ubiquitination in human diseases.'