Ubiquitine ligase

Résumé

L’ubiquitine ligase, ou ubiquitine ligase E3, est une ligase qui catalyse la réaction : :ATP + ubiquitine + lysine–proteine AMP + diphosphate + N-ubiquityllysine–protéine. Cette enzyme recrute l' E2 chargée en ubiquitine, reconnaît une protéine substrat, et assiste ou catalyse directement le transfert de l'ubiquitine de l'enzyme E2 vers la protéine substrat. L'ubiquitine est liée à un résidu de lysine sur la protéine cible par une liaison isopeptidique. Les ligases E3 interagissent à la fois avec la protéine cible et l'enzyme E2 et détermine la spécificité de l'enzyme E2 pour certains substrats. Les ligases E3 réalisent généralement l'ubiquitination de leur substrat avec des chaînes d'ubiquitine liées au résidu Lys48 en vue de leur destruction par le protéasome. Cependant, il existe de nombreux autres modes de liaison, qui modifient l'activité, les interactions ou la localisation d'une protéine. L'ubiquitination des protéines par les ligases E3 intervient dans la régulation de nomb

Source officielle

https://fr.wikipedia.org/wiki/Ubiquitine_ligase

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Excessive levels of saturated fatty acids are toxic to cells, although the basis for this lipotoxicity remains incompletely understood. Here, we analyzed the transcriptome, lipidome, and genetic interactions of human leukemia cells exposed to palmitate. Palmitate treatment increased saturated glycerolipids, accompanied by a transcriptional stress response, including upregulation of the endoplasmic reticulum (ER) stress response. A comprehensive genome-wide short hairpin RNA (shRNA) screen identified >350 genes modulating lipotoxicity. Among previously unknown genetic modifiers of lipotoxicity, depletion of RNF213, a putative ubiquitin ligase mutated in Moyamoya vascular disease, protected cells from lipotoxicity. On a broader level, integration of our comprehensive datasets revealed that changes in di-saturated glycerolipids, but not other lipid classes, are central to lipotoxicity in this model. Consistent with this, inhibition of ER-localized glycerol-3-phosphate acyltransferase activity protected from all aspects of lipotoxicity. Identification of genes modulating the response to saturated fatty acids may reveal novel therapeutic strategies for treating metabolic diseases linked to lipotoxicity.

CELL PRESS2019

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Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6

Michal Feldman Elmalam, Laurence Gouzi Abrami, Béatrice Kunz, Elsa Anne Perrody, Françoise Gisou van der Goot Grunberg

Many membrane proteins fold inefficiently and require the help of enzymes and chaperones. Here we reveal a novel folding assistance system that operates on membrane proteins from the cytosolic side of the endoplasmic reticulum (ER). We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19. This ubiquitination-deubiquitination is conceptually reminiscent of the glucosylation-deglucosylation occurring in the ER lumen during the calnexin/calreticulin folding cycle. To avoid infinite futile cycles, folded LRP6 molecules undergo palmitoylation and ER export, while unsuccessfully folded proteins are, with time, polyubiquitinated on other lysines and targeted to degradation. This ubiquitin-dependent folding system also controls the proteostasis of other membrane proteins as CFTR and anthrax toxin receptor 2, two poor folders involved in severe human diseases.

Elife Sciences Publications Ltd2016

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Novel ubiquitin-dependent quality control in the endoplasmic reticulum

Michal Feldman Elmalam, Françoise Gisou van der Goot Grunberg

Proteins of the endomembrane system undergo assisted folding in the endoplasmic reticulum (ER), then quality-control and, if misfolded, ER-associated degradation (ERAD). Recent findings on the biogenesis of a type-I membrane protein (an LRP6 mutant) lead us to hypothesize the existence of a novel mechanism promoting folding of membrane proteins from the cytosolic side of the ER. The proposed folding mechanism involves cycles of chaperone binding through mono-ubiquitylation and de-ubiquitylation, followed eventually by poly-ubiquitylation and ERAD. This suggests a novel dual role for ubiquitylation in the ER - dependent on the type of ubiquitin chains involved - in folding and in degradation, and highlights the potential importance of de-ubiquitylating enzymes.

Elsevier2009

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