Tetraspanin TSP-12 and SUP-17/ADAM10 exhibit cell type–specific codependence for trafficking through the Golgi

A subset of the four-pass transmembrane proteins called C8 tetraspanins (TspanC8) can bind and promote the cell surface localization of ADAM10 (A Disintegrin and Metalloproteinase 10). ADAM10 is a conserved transmembrane metalloprotease essential for metazoan embryonic development and human health. However, the in vivo functional relationships between C8 tetraspanins and ADAM10 are not fully understood. <i>Caenorhabditis elegans</i> has two paralogous tetraspanins, TSP-12 and TSP-14, that resemble the mammalian TspanC8 proteins. We have previously shown that TSP-12/TspanC8 can bind SUP-17/ADAM10 and promote its cell surface localization in early embryos. In this study, we identified the specific step in the secretory pathway where TSP-12-SUP-17 interaction is needed. We found that TSP-12 and SUP-17 share a mutually dependent, yet cell type- and developmental stage-specific relationship in their Golgi trafficking itinerary. In the early embryo, TSP-12 and SUP-17 depend on each other for their transit through the Golgi. However, only SUP-17 is required for proper Golgi trafficking of TSP-12 in the developing oocytes. We further showed that the ER accumulation of SUP-17 in embryos lacking TSP-12 is mediated by the Retention in Endoplasmic Reticulum 1 protein RER-1. These findings, combined with our previous work showing that TSP-12 and TSP-14 function redundantly in endosomes for the recycling of the type II receptor of the BMP signaling pathway, showcase the dynamic and versatile functions of TSP-12 in membrane trafficking in specific cellular contexts. They further highlight the importance of dissecting the functional relationships between TspanC8 proteins and ADAM10 in vivo.