Proposed model for regulation of cell-surface expression of tetraspanins. Several genes were identified to play a role in regulation of tetraspanin trafficking from sequential genome-wide loss-of-function CRISPR-Cas9 screens. TMEM208 is localized at the ER, and the rest are resident in the Golgi apparatus. In wild-type cells, tetraspanin proteins are modified by N-glycosylation and traffic to the cell surface. Their internalization into the cells occurs at a slow rate. In the absence of MGAT1/2, the N-glycosylation modification of tetraspanin proteins is blocked, and their internalization is facilitated. Release from the Golgi apparatus membrane and subsequent degradation is an important mechanism for keeping B3GNT5 at a low level in cells. In the absence of SPPL3, a large amount of FL and functional B3GNT5 protein is retained in the Golgi apparatus membrane, which, in turn, leads to high expression of nLc4 in the plasma membrane and accelerates endocytosis of tetraspanin proteins.
