The CoV spike (S) glycoprotein serves as another example of a viral surface glycoprotein associated with UPR activation. It is the largest structural protein of CoV and is heavily glycosylated. Like many viral surface glycoproteins, the S protein mediates cellular attachment and possesses fusion activity that permits cell entry. The cellular target for the S protein varies across different CoV strains. During CoV infection the S protein activates the UPR, although the underlying mechanisms are strain specific . Expression of SARS-CoV-1 S is linked to activation of the PERK pathway, increasing expression of ER stress chaperones . The PERK pathway is similarly induced by HCoV-HKU1 S. However, although PERK activation can be attributed to a central region spanning amino acids 201-400 on the S1 subunit of the SARS-CoV-1 S protein, this is not the case for HCoV-HKU1 S . This speaks to independently evolved tendencies to activate PERK across the various CoV strains. That activation of the UPR from the S protein of SARS-CoV-1 and SARS-CoV-2 can be attributed specifically to regions of the S1 subunit suggests that in the case of the S protein, glycosylation is not critical for UPR activation .