An endosomal protein complex regulates Notch signaling by promoting Notch receptor recycling to the cell surface, Li et al. reveal.
The 10 members of the COMMD protein family are conserved from protozoans to humans. COMMD1 assembles with several endosomal proteins to form a “CCC” complex that promotes delivery of the copper transporter ATP7A to the plasma membrane. Whether other COMMD proteins act similarly to regulate the endosomal sorting of other membrane proteins remains unclear.
Li et al. found that COMMD9—whose gene is deleted in patients with WAGR syndrome—interacts with CCC subunits and with members of the Notch receptor family. Notch surface levels were reduced in cells lacking COMMD9; the receptors were instead retained in endosomes and delivered to lysosomes for degradation, resulting in decreased activation of the Notch signaling pathway. Accordingly, mice lacking Commd9 developed cardiovascular defects similar to Notch-deficient animals and died during embryogenesis.
CCC complexes appear to incorporate multiple COMMD proteins and link them to key components of the endosomal sorting machinery. COMMD9 preferentially interacted with COMMD5 and COMMD10, and depleting COMMD5 also impaired Notch receptor trafficking to the plasma membrane. Senior author Ezra Burstein thinks that different combinations of COMMD proteins may act as sorting receptors for specific endosomal cargoes. Alternatively, the various family members could operate at distinct stages of the endocytic and secretory pathways.