Tetraspanin CD9, but not tetraspanin CD81, associates with DPP4 and the type II TM serine protease (TTSP) member TMPRSS2, a CoV-activating protease, to form a cell surface complex [131]. This CD9–DPP4–TMPRSS2 complex permits MERS-CoV pseudovirus entrance into the host cells. The tetraspanins have four TM spanning regions linked by one large and one small loop in the extracellular region. Tetraspanins form virus entry baselines and open CoV entry routes. To help viral entry into host cells, MERS-CoV S interacts with DPP4 receptors via the RBD. Receptor involvement causes cleavage using proteases such as the previously described TMPRSS2. Association of tetraspanin CD9 with the DPP4–TMPRSS2 complex triggers the S glycoprotein. MERS-CoVs enter the cells via endocytosis and cathepsins cleave the S proteins [132].