Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling

Haiying Li, Yeon Koo, Xicheng Mao, Luis Sifuentes-Dominguez, Lindsey L. Morris, Da Jia, Naoteru Miyata, Rebecca A. Faulkner, Jan M. van Deursen, Marc Vooijs, Daniel D. Billadeau, Bart van de Sluis, Orane Cleaver, Ezra Burstein*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Web of Science)

Abstract

Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD-CCDC22-CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family.
Original languageEnglish
Pages (from-to)605-617
JournalJournal of Cell Biology
Volume211
Issue number3
DOIs
Publication statusPublished - 9 Nov 2015

Cite this