“…Influenza hemagglutinin (HA) is a uniquely attractive model protein for systematically and quantitatively evaluating whether and how ER proteostasis mechanisms impact client protein mutational tolerance. The folding of HA is perhaps as well-delineated as for any other membrane protein, and HA interacts extensively with components of the host cell’s ER proteostasis network ( Chen et al, 1995 ; Daniels et al, 2003 ; Sauter et al, 1992 ; Nakajima et al, 1986 ; Frabutt et al, 2018 ; Hurtley et al, 1989 ; Hebert et al, 1997 ; Ueda and Sugiura, 1984 ; Skehel and Wiley, 2000 ; Klein et al, 2018 ; Gamblin et al, 2004 ; Pankow et al, 2015 ). Co-translationally, HA is heavily N -glycosylated and engages the ER’s lectin chaperones, calnexin and calreticulin, which increase HA’s folding efficiency and prevent misfolding ( Chen et al, 1995 ; Daniels et al, 2003 ; Hebert et al, 1997 ).…”