scholarly journals The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein–coupled receptor CXCR4

2014 ◽  
Vol 25 (12) ◽  
pp. 1892-1904 ◽  
Author(s):  
Justine Holleman ◽  
Adriano Marchese

G protein–coupled receptor (GPCR) sorting into the degradative pathway is important for limiting the duration and magnitude of signaling. Agonist activation of the GPCR CXCR4 induces its rapid ubiquitination and sorting to lysosomes via the endosomal sorting complex required for transport (ESCRT) pathway. We recently reported that ESCRT-0 ubiquitination is linked to the efficiency with which CXCR4 is sorted for lysosomal degradation; however mechanistic insight is lacking. Here we define a novel role for the really interesting new gene–domain E3 ubiquitin ligase deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes. We show that DTX3L localizes to early endosomes upon CXCR4 activation and interacts directly with and inhibits the activity of the E3 ubiquitin ligase atrophin-1 interacting protein 4. This serves to limit the extent to which ESCRT-0 is ubiquitinated and is able to sort CXCR4 for lysosomal degradation. Therefore we define a novel role for DTX3L in GPCR endosomal sorting and reveal an unprecedented link between two distinct E3 ubiquitin ligases to control the activity of the ESCRT machinery.

2003 ◽  
Vol 5 (5) ◽  
pp. 709-722 ◽  
Author(s):  
Adriano Marchese ◽  
Camilla Raiborg ◽  
Francesca Santini ◽  
James H Keen ◽  
Harald Stenmark ◽  
...  

2002 ◽  
Vol 109 (1-3) ◽  
pp. 173-179 ◽  
Author(s):  
Giulio Innamorati ◽  
Michael Insuk Whang ◽  
Raffaella Molteni ◽  
Christian Le Gouill ◽  
Mariel Birnbaumer

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Tao Zhang ◽  
Kangyun Dong ◽  
Wei Liang ◽  
Daichao Xu ◽  
Hongguang Xia ◽  
...  

Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. In this study, we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of G-protein-coupled receptor (GPCR) ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington's disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.


Cell Reports ◽  
2016 ◽  
Vol 17 (10) ◽  
pp. 2532-2541 ◽  
Author(s):  
Syamantak Majumder ◽  
GuoFu Zhu ◽  
Xiangbin Xu ◽  
Sharon Senchanthisai ◽  
Dongyang Jiang ◽  
...  

Glia ◽  
2015 ◽  
Vol 63 (12) ◽  
pp. 2327-2339 ◽  
Author(s):  
Marta Fumagalli ◽  
Elisabetta Bonfanti ◽  
Simona Daniele ◽  
Elisa Zappelli ◽  
Davide Lecca ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document