TMPRSS2-cleaved ACE2 is involved in SARS-CoV and MERS-CoV infections. SARS-CoV-2 uses ACE2 for cell entry through TMPRSS2 priming of the S glycoprotein (Figure 7). Infection of the H7N9 influenza and H1N1 influenza A subtype viruses are also mediated by TMPRSS2-cleaved ACE2. This implies that TMPRSS2 can be targeted as a strategic antiviral therapy [92]. Transmembrane protease serine 2, termed TMPRSS2, a type II TM Ser protease (TTSP), also cleaves ACE2. The human TMPRSS2 gene, located on chromosome 21, comprises androgen receptor elements (AREs) in the upstream 5′-flanking region [93]. TMPRSS2 expression is regulated in an androgen-dependent manner. The TMPRSS2 gene encodes 492 amino acids. The original form is cleaved into the major membrane form and the minor soluble form. TMPRSS2 activates protease activated receptor 2 (PAR-2) and activated PAR-2 upregulates matrix metalloproteinase-2 (MMP-2) and MMP-9. TMPRSS2-activated hepatocyte growth factor (HGF) induces c-Met receptor signaling. TMPRSS2 activates SARS-CoV and MERS-CoV. The SARS-CoV S glycoprotein is cleaved by host-borne TMPRSS2, human airway trypsin-like protease (HAT), TM protease, serine 13 (MSPL), serine protease DESC1 (DESC1), furin, factor Xa and endosomal cathepsin L/B. SARS-CoV can enter cells upon cleavage by protease TMPRSS2 or endosomal cathepsin L/B [90]. Virus S protein precursor is cleaved by host proteases. The spikes are cleaved by endosomal cathepsin and by Golgi or plasma membrane TMPRSS2 in the step of assembly or attachment and release. The serine protease inhibitor camostat effectively blocks lethal SARS-CoV infection to mice. However, serine protease and cathepsin inhibitors are not effective. Thus, TMPRSS2 is suggested to be an acting protease for SARS-CoV entry into host cells, but not by cathepsin. Cis-cleavage liberates SARS-CoV S glycoprotein fragments into the extracellular supernatant. Trans-cleavage activates the SARS-CoV S glycoprotein on the target cells, potentiating efficient SARS-CoV S glycoprotein-driven viral fusion. TMPRSS2-activated SARS-CoV facilitates enveloped virus entry into cells. TMPRSS2 is important for SARS-CoV entry and infection [81,94,95,96].