ER chloride channel CLCC1 promotes nuclear envelope fusion in herpesviruses and their hosts

Herpesvirales is an ancient viral order that infects species ranging from mollusks to humans, with lifelong persistence. They export their capsids from the nucleus to the cytoplasm by a noncanonical nuclear egress route that involves capsid budding at the inner nuclear membrane followed by fusion of this temporary envelope with the outer nuclear membrane. Here, using a whole-genome CRISPR screen, we identified ER protein CLCC1 as important for the fusion stage of nuclear egress herpes simplex virus 1. We also found that the genomes of Herpesvirales that infect mollusks and fish encode CLCC1 genes acquired from host genomes via horizontal gene transfer. In uninfected cells, loss of CLCC1 causes a nuclear blebbing defect, suggesting a role in host nuclear export. We hypothesize that CLCC1 facilitates an ancient cellular membrane fusion mechanism that Herpesvirales have hijacked or co-opted for capsid export. Structural analysis suggests that CLCC1 oligomerization into membrane-bound rings could promote membrane remodeling.