Consistent with a direct relationship between TFEB activation, IFITM2/-3 turnover, and spike-mediated cell entry, we found that ectopic expression of a constitutively active form of TFEB lacking the first 30 amino-terminal residues (51) was sufficient to both trigger IFITM2/-3 loss from cells (Figure 6E) and increase susceptibility to HIV-CoV-2 infection (Figure 6F). Here, IFITM2 is linked to COVID-19.